Léo Ramos Chaves / Revista Pesquisa FAPESPBianco at Mackenzie Presbyterian University, during a visit to São Paulo in AprilLéo Ramos Chaves / Revista Pesquisa FAPESP
Around 15 years ago, Brazilian physician Antonio Carlos Bianco noticed that something was not going well with the treatment for hypothyroidism that was being used at the time in different countries. Based on his research, he concluded that changes were needed. A professor at the University of Miami in the USA at the time, he treated women who were taking the medication recommended for the problem and who did not improve. Since the 1970s, therapy has consisted of using a synthetic version of the hormone thyroxine (T4), developed by US pharmaceutical companies to address malfunction of the thyroid — the butterfly-shaped gland located in the neck.
In experiments performed in his laboratory, Bianco and his team found that treatment with T4 did not normalize the action of thyroid hormones on the body for many patients, and that many people with hypothyroidism were unable to convert T4, an inactive compound, into T3, triiodothyronine, the hormone that works. The solution, as he proposes, is to add a synthetic version of T3 to their treatment.
With around 300 scientific articles published, cited over 30,000 times by other works, Bianco is an international authority on studying the thyroid and presented his discoveries about this fault in the treatment in the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do, published in 2022 in the USA.
Field of expertise
Thyroid disease
Institution
University of Chicago
Educational background
Undergraduate degree in medicine at the School of Medical Sciences of Santa Casa de São Paulo (1983), master’s (1985) and PhD (1988) in physiology at the University of São Paulo (USP)
A graduate from the Santa Casa de São Paulo School of Medical Sciences, he completed his master’s and PhD at the University of São Paulo (USP), where he became a professor. In the late 1990s, he moved to the USA and began the US phase of his academic career at the prestigious Harvard University.
In April, Bianco was in São Paulo for a conference at the FAPESP headquarters about training physician-scientists, a rare professional group in Brazil. The father of triplets, now 22 years old, he spoke with Pesquisa FAPESP at Mackenzie Presbyterian University, where his wife, biologist and researcher Miriam Oliveira Ribeiro, is studying the neuroendocrine control of behavior.
What are the most common diseases linked to the thyroid?
The most common is hypothyroidism, which frequently occurs when the gland is destroyed by an autoimmune process or is removed due to nodules. This and other problems in the thyroid affect more women than men, at a ratio of 9 to 1. This occurs because autoimmune diseases, which also affect the thyroid, are more frequent in women. We still don’t know what the specific mechanism behind this is. In the USA, there are around 20 million people with hypothyroidism; in Brazil, there are maybe 10 million. Until 1970, the treatment consisted of taking a pill with pig thyroid extract every day. It worked reasonably well. The current treatment, with T4 hormone, works well, but is not effective for 10% to 20% of people.
Why?
T4 is not an active substance. It needs to be activated in the body by conversion into T3. With the discovery in 1970 that our body could convert T4 into T3, the therapeutic approach changed. We began treating patients with only synthetic T4. It was a huge change because the thyroid extract contains both hormones. At that time, pharmaceutical companies used these findings and did intense marketing in favor of the new approach. They convinced physicians that the pig thyroid was something old and that the treatment could be done with just synthetic T4. After 1970, patients began to appear who did not feel completely cured, even taking the correct dose of T4. The recommendation that I received from my professors was to send these patients, middle-aged women in general, for psychotherapy. The physicians alleged that they were having an existential crisis. It was what I did for a good part of my professional life. Until the day when I treated a woman who was a professor in Miami and told me: “I was diagnosed with hypothyroidism, began taking the indicated medicine and didn’t return to normal. I lost my job.” I told her: “Your exams are good. You should do psychotherapy.” She began crying and left. The following week, another female professor came and told me the same story: “I can’t give classes anymore; I’ve quit my job.”
What happened to these people?
They had brain fog, mental confusion. I thought: “Something is wrong.” I went to the laboratory and began studying the problem. I changed the focus of my research to analyze how thyroid hormones affect the brain and reasoning abilities. The thyroid naturally produces T3 and T4. T3 is the active hormone; T4 is the inactive prohormone that can be activated by the enzyme deiodinase, which I have studied since the start of my professional life. In hypothyroid treatment, the T4 from the medication is absorbed by the blood and transformed into T3 in the tissues containing deiodinase. But the final concentration is lower than would occur naturally. This deficiency can be aggravated, in some people, because the deiodinase does not function well due to a genetic polymorphism. For them, it is necessary to add T3.
For these patients, the pill with the extract was more effective.
Exactly, because of the two hormones. After almost 15 years studying the issue, I wrote the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do. The pharmaceutical companies that sold the synthetic T4 conducted million-dollar marketing campaigns with physicians, medical associations, and patient support groups. They had an enormous influence on the physicians and professional associations related to the thyroid field. To have an idea, synthetic T4 was approved by the FDA [US Food and Drug Administration] without its efficacy and safety having been determined in randomized clinical studies.
The current treatment of hypothyroidism is not effective for those who are unable to convert the T4 hormone into its active form
How did it manage that?
I don’t know the details. At the time, medical leaders from the thyroid field, including managers of medical-professional associations, wrote to the FDA supporting the approval. I mention this in the book. For those who do not respond well to T4 alone, a good solution is combining T4 with T3. My colleagues and I have already discussed this extensively and many things have changed. Currently, medical associations in the USA and Europe recommend using both hormones for this group of symptomatic patients.
Do physicians accept the idea?
The younger ones understand. The older ones do not easily accept it; they have suffered from the same brain washing as I did in the past. The behavior of the pharmaceutical industry has been interesting. It continues making huge profits because synthetic T4 works well in most cases. But it has already repositioned itself to reach the patients who benefit from the addition of T3 to the treatment. Today, in the USA, around 2 million people use therapy with T4 and T3, the majority based on pig thyroid extract. This number has doubled in the last 10 years. I am a consultant for some pharmaceutical companies in the field and I thought it would create an awkward situation when I published the book, but they were excited about the new market.
Did you take your undergraduate degree in medicine already thinking about doing research?
I studied medicine at Santa Casa due to the influence of my brother, Salvador Bianco, a retired professor from the Department of Psychiatry at UNIFESP [Federal University of São Paulo] who is 10 years older than me. Since the beginning, I wanted to become a researcher. Alongside Santa Casa, I studied biology at USP but gave up in the last year because botany was boring. Afterwards, I did my master’s and PhD in USP’s Institute of Biomedical Sciences. In the first year of medicine, I began asking where research was conducted and they responded: “Go to physiology, where professor Carlos Roberto Douglas is.” At first, he, who died a few years ago, didn’t agree: “You are in the first year, you don’t know anything; you need to wait a little and come back next year.” I insisted and he gave in. I started assisting people from the group who were studying the effects of nutrition on the thyroid. This was in 1978. I never stopped since then. It was a coincidence that I came across this topic.
You obviously liked it, otherwise you would have abandoned it.
Without doubt. At that time, maybe 10% or 20% of the patients I saw in the outpatient clinic at Santa Casa had goiter, because of iodine deficiency.
Was there no salt with iodine at the time?
Before the 1970s it was already recommended that table salt be iodized. But there was not much engagement from the salt industry or health surveillance supervision. The situation began to improve with the work that endocrinologist Geraldo A. de Medeiros-Neto [1935–2022] did with politician André Franco Montoro [1916–1999], when the latter was senator [1971 to 1983]. Only from then was there more engagement from the government in overseeing salt iodization. It is not as easy a task as it appears. The salt passes on a conveyor belt, and an iodine solution has to be sprayed onto it. It has to be the correct amount, well calculated, because iodine evaporates over time. Therefore, when cooking, you shouldn’t keep the salt close to the stove or in a hot place because it accelerates evaporation.
Is the goiter endemic still a problem in Brazil?
Not anymore. The actions of endocrinologists and health surveillance were effective. But there will always be an iodine deficiency in the soil, and consequently, in food. This deficiency is geographic; it occurs in almost the entire world. The thyroid needs iodine to produce its hormones. When we consume iodine in the diet, it is absorbed by the blood and reaches the thyroid. If there is little iodine in the blood, the gland starts to grow in an attempt to capture more. It normally weights 20 grams, but can reach almost 1 kilo because its cells multiply to absorb the little iodine available. It is a compensation mechanism. Now, if the lack of iodine is intense to the point of the goiter not being able to compensate it, hypothyroidism can occur. There is still a mild to moderate deficiency or shortage in several regions of the world. The shortage is intense in a few regions. Those at risk of being affected by an iodine shortage are children and pregnant women. Children because their compensation mechanisms are not as efficient, and pregnant women because during pregnancy, they can lose more iodine due to adjustments in the physiology of the thyroid.
What can iodine deficiency cause in pregnancy?
If it is intense enough to harm the synthesis of hormones in both the mother and fetus, it can lead to goiter and to fetal hypothyroidism. The mother’s body is capable of compensating the deficiency, but, for the developing baby, the lack of iodine is a serious problem. The thyroid hormones are very important for the brain development of the fetus and newborn baby. So much so that a heel prick test is routinely performed to check for genetic problems that affect the development and functioning of the thyroid, which affect one in every 2,500 live births.
Why are these hormones so important from pregnancy?
Mainly for neurogenesis, right at the beginning of the brain development, when the neurons are formed. This is one of the topics that we study in my laboratory. The lack of thyroid hormone at the beginning of life triggers epigenetic mechanisms that permanently modify the expression of many genes throughout the body. It is not possible to correct it later on. Nowadays, this is the topic that takes up most of my time: understanding how T3, or the lack of it, modifies genetic expression.
What have you discovered so far?
We have created a mouse that presents localized hypothyroidism in the liver, just in the first two days of life. The animal develops normally, but when it reaches adulthood, the functioning of its liver is different from that of the liver of an animal that did not have hypothyroidism immediately after birth. The liver loses the capacity to store fat, producing more ketone bodies and less glucose. This is because the folding of chromatin [the strand of DNA in the nucleus of cells], which regulates the expression of genes, is modified by the thyroid hormone.
To be successful in the USA, a researcher needs to be independent and have their own grants
You graduated from Santa Casa and became a professor at USP. Do you have any connection with UNIFESP?
I have close friends and colleagues at USP and at UNIFESP. One of my mentors in São Paulo was professor Rui Monteiro de Barros Maciel, of UNIFESP. We still collaborate today. In 1984, he introduced me to Chilean researcher J. Enrique Silva, through whom I went to Harvard. I have never worked at UNIFESP, despite being an accredited professor on the graduate course in endocrinology there to this day, and I have already supervised several PhD students. At USP, I was a professor in the Department of Physiology and Biophysics of the Institute of Biomedical Sciences [ICB] for 15 years.
How did the possibility of going to Harvard arise?
During my master’s, I went to an endocrinology congress in Canela, in Rio Grande do Sul. There, Rui introduced me to Enrique, who worked at Brigham and Women’s Hospital, of Harvard University, in Boston, and didn’t want to go back to Chile because of the military coup. I told Enrique: “I want to go to your laboratory.” I did my PhD at ICB, with the experimental part in Harvard. Fifteen years later, I decided to visit Harvard again. As Enrique no longer worked there, I called professor Philip Reed Larson, who had been his mentor, and was accepted. I spent 10 years in Boston, established my laboratory and became head of the thyroid sector of the Brigham and Women’s Hospital. Becoming independent was one of the biggest challenges of my move to the USA.
Why?
To be successful and recognized by colleagues, a researcher needs to be independent and have their own grants. I went in 1998, without a grant, and worked in Larson’s laboratory, who was the PI [principal investigator]. This arrangement is perfect for someone doing a postdoctoral fellowship or who is a visiting professor, because the functioning of the laboratory and the salaries are funded by the PI. As the stay lengthens, this setup becomes less advantageous because it is necessary to work on what the PI is willing to fund, and the salary is restricted.
In this case, will you always be a postdoctoral fellow or are you able to have a position?
It’s possible to be a university professor, but until you become independent, you will always be linked to a PI. And, if they lose the grants, it’s over.
Is it the PI who defines how much they will pay those who work with them?
Yes. My first salary was very low, around US$6,000 per year. There is still a very strong trend today of paying less than the market rate to visiting researchers. They generally don’t know the local standards and don’t wish to create a situation by complaining because they understand the visit is temporary and the alternative is taking the return flight.
How do you have success in research in the USA?
The researcher needs to disconnect themselves from the PI and become an independent researcher with their own grants and laboratory, which transforms them into an asset of the university. As a postdoctoral fellow, the university thanks you for the cheap labor, and nothing more. It is interested in the principal investigator because, together with the funding that they can get, lots of money comes to the university. If I’m a principal investigator and manage to get a US$250,000 grant from the NIH [US National Institutes of Health], the standard value of a modular grant, the NIH pays a very high additional rate, known as “indirect costs,” to the university. This rate depends on the agreement between the university and the NIH. Harvard receives around 70%. Only around 10% of the grants requested from the NIH are funded, which gives you an idea of how difficult it is to become an independent researcher.
How do you compare your life abroad with the time that you were at USP?
At USP, I did research but also taught many classes. At Harvard, I taught one class a year on the medicine course, about the thyroid. At the University of Chicago too. When producing the course program, the coordinator chooses from the best in each area. In these large institutions you find the best professors in every or almost every field. It is a tremendous prestige to teach a class.
It is a different system in Brazil.
At Harvard, there are very few students for the number of professors. There, in the school of medicine, there were around 11,000 professors. I’m not exaggerating. There are several affiliate hospitals, where many professionals work. One difficulty that I had in Brazil to do research was the process for importing reagents, animals, etc. The bureaucracy got in the way. The USA is like Disneyland for researchers. The order is made on the computer today and tomorrow arrives by FedEx.
That is the good side…
My boss was always an excellent researcher, a world leader in the thyroid field. So he didn’t have very much difficulty renewing his grants. I had to reinvent myself to be able to write the grant requests, obtain funding, have my own laboratory, and become independent. The competition is extremely fierce, with the entire USA, with the best researchers. I was lucky and obtained many grants. I quickly received job offers to leave Harvard and ended up becoming head of endocrinology at the University of Miami. This extremely competitive system appears to be really good, but it deserves a word of warning. It encourages the formation and establishment of individuals and centers of excellence, but at what price?
What do you have to do to sell yourself successfully?
You need to have a lot of objectivity and develop your own formula. It is an art. It took a long time, but I managed it. This is the bottleneck that the majority don’t pass through. For almost 10 years, I have been going to the NIH to judge the grant requests in the cellular and molecular endocrinology sector. At the end, I return home depressed from seeing so many good people have their requests rejected and knowing the professional and personal implications involved.
It would be fantastic to train physician-scientists in Brazil with clinical and basic research knowledge
Why did you leave Harvard?
During a certain period in the life of a researcher, being in a university like Harvard is very important. It helps with training and peer recognition. Over time, the importance diminishes. Additionally, the more famous the university, the lower the salary. There is the “Harvard salary” factor: “I earn little, but I work at Harvard.” Other good universities, with less prestige, want to attract good researchers, who bring their grants, and pay more competitive salaries. This exchange is a key career moment, which must be very well studied. I received a very good offer to go to Miami and the opportunity to run the endocrinology service, which made me accept it. It was fantastic. I should have gone earlier. My training lacked the vision and understanding of the business behind research and academic medicine in the USA.
What changed?
In Miami, I had an administrative role with more responsibilities. I was the head of the endocrinology service of three hospitals, with around 20 endocrinology physicians and eight residents. In this structure, the head can do almost everything. Hire, fire, decide people’s workload and salary. It is not like the Brazilian structure, which is very rigid. What can the head of a public university such as USP decide? Very little. Nobody’s salary changes and they cannot reconfigure the service quickly with new professors. They take on a more bureaucratic role of providing a presence and making sure the workload of classes and patient care is fulfilled. There, the head molds the service as they wish. If it doesn’t work, they are substituted. I owe my success in research to my mentors and to Harvard. In Miami, I learned to administer the medical field.
Were you able to do research as well?
I was. I have been in the USA almost 30 years and have never stopped researching. But Miami is not Harvard. I learned to get my hands dirty, to do everything and to improvise. After six years, the opportunity arose to move to Chicago. Not because of my research qualities, but my administrative ones. I went as the president of a group of around 600 physicians to Rush University, a private institution that has a large hospital in Chicago. There, everything changed.
Why?
Because behind the scenes of a large hospital is a mess, often frightening. I went from leading 20 physicians, to 600. I learned the business of medicine and the workings of a large hospital. I learned how the different parts interconnect and make the machine work. It was stressful. I would hear from the CEO of the hospital: “You have to make the physicians work more,” and “their salaries are too high.” From the physicians, I would hear: “We are working too much,” and “we want a raise.” I was responsible for a budget of around US$300 million a year. After four years, I decided to leave. I learned a lot, but the level of stress was extremely high.
And where did you go?
To the University of Chicago, where I don’t have an administrative role. My work is doing research. Professionally, I have never been so happy and productive.
What is the parallel between what happens in the USA and here?
I have some idea of how Brazilian institutions work because of my association with the people from UNIFESP and USP and my wife, Miriam, who is a biologist and professor at Mackenzie Presbyterian University. In general, I feel that younger people have less interest in scientific areas nowadays. It is not just a Brazilian phenomenon. It wasn’t like this when I started out. There was a thirst for wanting to do and learn a lot. I believe that this lack of interest is, in part, motivated by social changes that prioritize quality of life. As a postgraduate, my colleagues and I worked a lot, with little reward. I don’t see this in my students today. Besides this, with rare exceptions, the salary for doing research in the USA is very low, and graduates finish university in debt to the institution’s grant program. This means that the interest in better paid positions, far from research, is huge.
Is it different in Brazil?
I don’t know the situation in Brazil very well, but one difference is that there has always been the idea here that a physician who is a university professor and researcher has a private clinic. This disrupts the continuity of research. In the USA, it doesn’t exist. Professors work 100% of the time doing research and seeing patients in the university. Physicians are prohibited to attend outside the university in which they work. In my case, I am an employee of the University of Chicago and they pay 100% of my salary, regardless of my area of work. But I can do consultation for pharmaceutical companies, legal firms involved in litigation between physicians and patients, patents, etc. There is no problem with that. We all have 20% of time to work on consulting activities. We have the obligation to inform the university about the topic and the amount received from these consultations, so that any conflicts of interest can be resolved.
In the lecture that you gave at FAPESP, you covered the question of the physician-researcher.
I talked about the training of the physician-scientist, a subfield of medicine in the USA that covers physicians with excellent clinical and basic research knowledge. The majority of physician-scientists in the USA have an MD and PhD. The medicine course is twice as long for them, but they graduate with both titles. In Brazil, many physicians take postgraduate courses after residency. One fundamental difference is that, in the USA, the PhD is obtained in a basic subject. In Brazil, PhDs for physicians are usually in a clinical subject. We train superclinicians and not physician-scientists.
In any case, it is difficult to reproduce the US model.
The annual budget of the NIH is US$50 billion. They invest half a billion in training physician-scientists. It would be fantastic to encourage the training of physician-scientists in Brazil, even on a small scale. For this, we need to think about paying a suitable institutional salary so that the physicians dedicated to academia can remain in the hospital all the time. Maybe the research funding agencies could implement something similar in Brazil, even if it were a pilot project.
