ATG Newsletter Issue 04
December 2016
Welcome to another edition of the ATG Member Newsletter!
1
Cancers
ur bodies often work as orchestras. All the cells work at their best to assure that their music is harmonious and homeostasis prevails. This extraordinary group effort does not condone protagonists; it tends to be so seamlessly orchestrated that we often forget that it is performed by so many different cells.
O
Nonetheless, there comes a day when the music no longer feels unisonous, and we are reminded of our multicellularity. Some of the players may, for instance, underperform because they are affected by a microrganism or another malaise. Fortunately, most of those disruptions are temporary and ultimately the harmonious music restarts. ATG Newsletter
Issue 04 December, 2016 Contributors: Ana Rita Araujo, Helder F. Araujo (Ed.), Maria De Sousa, Filipa Ferreira, Eurico Morais de Sรก, Pedro Resende, Catarina Seabra & Andre Sousa. Cover: Helder F. Araujo. Linguistic revision: Panthea Heydari www.agtnewsletter.up.pt atgsnewsletter@gmail.com ATG - All Time GABBA The Alumni Association of the Graduate Program in Areas of Basic and Applied Biology University of Porto - Portugal www.atg.up.pt ATG - GABBA IPATIMUP Rua Dr. Roberto Frias s/n 4200-465 Porto Portugal geral@atg.up.pt
Cancer is a particularly threatening disruption. Some of players surreptitiously become dissidents and insisit on playing their own sounds. As much as this cacophony is often felt as menacing, it is not always fatal. Depending on different factors, the dissidents may be detained, and the feeling of a unisonous body is experienced again. Fortunately, this seems to be the outcome for more and more cancers, but, in many cases, the worst still happens: the dissidents are so caught up by their own music that they, unintelligently, end up muting and destroying the body that supports them. This issue challenges us to think about the varied kinds of cancers and the different hosts. I hope you enjoy the challenge. As always, our sincere thanks to all of our contributors! This issue would not be possible without their help.
Helder F. Araujo
2
Contents Message from the President of the Executive Board Andre Sousa 5 De Sousa et al. Maria de Sousa & Manuel Sobrinho SimĂľes 7 City of Knowledge Part I. Citizens 28 Part II. Knowlegde 34 ATG News 42 GABBA News 45 Read and Highlighted 48
3
We hate to nag, but have you already become a member? To become a member, all you need to do is pay the annual dues, fill out the membership form, and email us the payment confirmation along with the membership form. You may please find the form on the website.
4
Message from the President of the Executive Board Andre Sousa
Dear colleagues, Two years passed by since we created our association and it is time to review what has been done and to plan the near future. After fulfilling all legal requirements and creating the proper tools to aggregate and contact all ATGs, we have been working on three main projects: Prémio ATG, Maria de Sousa Summer Research Program, and the GABBA Welcome Book. As I mentioned in our previous newsletter, we implemented the “Prémio ATG – All Time GABBAs”, which is awarded to high-school students participating in the “Ciência Viva no Laboratório” based on a report of their activities. We have received several applications. We, alongside Ciência Viva, are currently gathering jury members who will vote for the award winners. The awards will be given during our annual meeting in December.
We have made progress on on three projects: Prémio ATG Maria de Sousa Summer Research Program GABBA Welcome Handbook. But we still need your help.
We are also working on implementing the Summer Research Program. The first edition should happen in the summer of 2017. Since this initiative requires a more complex organization, we plan to host the first edition at University of Porto. If the event is successful, we will work on expanding it to other universities in Portugal and even abroad. Currently, we are discussing the logistics and funding for these events. We are trying our best to have the GABBA book ready for the 20th GABBA edition, but this will be very hard to accomplish without your help. During the last annual meeting, we all agreed that the book would be of great value for new and current students. However, only a very few ATGs ended up helping with the writing. We will contact some of you who already showed interest in helping with this task, but I would like to take this opportunity to encourage all members to get involved. If you are willing to help, please contact us. The main aims for the next years are to increase the number of members, to establish the Summer Research Program, and to become an Instituição de Utilidade Pública.
5
“The main aims for next two years: to increase the number of members, to establish the Summer Research Program, and to become an Instituição de Utilidade Pública.”
The first of those aims is particulary important. Without more members, it will be very difficult to achieve the other two aims. So far, ATG has been surviving with the hard work and monetary contributions of a very small number of people. The more people we have helping with the newsletter, the organization of our programs, and contributing as paying members of the association, the more successful our association will be. And, of course, as our association becomes successful, our members will enjoy more benefits. I would like to finish, as usual, by wishing good luck to all the GABBA students that are getting ready to defend their Ph.D. thesis and welcoming them to the ATG.
***
6
We know you are really busy with other impact factors, but your help would really have a major impact on ATG! ATG really needs your help! Send us an email when you are ready to help us, will you?
7
DE SOUSA ET AL. Cancer, The Emperor of All Maladies Interview with Maria de Sousa and Manuel Sobrinho Simões Anabela Mota Ribeiro
M
aria de Sousa, scientist, and Manuel Sobrinho Simões, pathologist, question the way science is conducted and talk about a disease that is part of ourselves, invades us and oftentimes kills us. It is a tough interview. Cancer or cancers? What stage? What host? What is the environmental trigger? A cancer is something that grows inside of us. It is like the twin we did not have when we were born. It is so successful that, “in its drive to survive and grow, the cancer eventually kills us and thus kills itself ”, says Manuel Sobrinho Simões no livro Gene, Célula, Ciência, Homem [Gene, Cell, Science and Man]. It is the emperor of all the maladies, as designated by Siddhartha Mukherjee in his book, “The Emperor of All Maladies: A Biography of Cancer”, published in 2010. “Cancer or cancers? What stage? What host? What is the environmental trigger? “
It is a representation of death, the ultimate word that remains unconquered, as Sopholes write in a poem translated into Portuguese by David Mourão Ferreira and cited by Maria de Sousa in her book “Meu Dito, Meu Escrito” [ My saying, My writing]: “Amid nature’s countless wonders none is found more marvelous than man. […]. Never an impasse as he marches on the future, only death, from death alone he will find no rescue”
This text is a translation* of the interview with Maria de Sousa and Manual Sobrinho Simões, published in the Portuguese newspaper Publico, July 26, 2015. https://www.publico.pt/ciencia/ noticia/cancro-o-imperador-detodos-os-males-1703017 *Translated by Helder Araujo
Colon and rectum, lung, and stomach cancers are associated with the highest mortality rates in Portugal in both genders. Breast cancer is the most fatal for women, and prostate cancer the most fatal for men. In 2010, 24, 917 people died of cancer in Portugal. Cancer kills. It does not always kill. It is foreseeable that more than half the world population will suffer from cancer in a near future (ten or twenty years from now). We might well get used to it.
8
This interview, which took place in the office of Portuguese Medical Association in Porto,was not easy for any of us. Why? Because we all know people who died of this disease and people who suffer from it and because we may all end up suffering from it – knowing this changes everything. It is thought that Hippocrates spread the word “cancer”, which derives from the Greek karkinos, the Greek word for crab. Crabs have a twofold and treacherous nature. And cancer may be regarded as an evil double of ourselves, a double that invades and attacks us. Do you think the word crab is still a good way to represent what cancer is? “[Cancer] is not only a double or traitor, but it also invades us. It invades from within.”
Manuel Sobrinho Simões (MSS) — Yes. It is not only a double or traitor, but it also invades us. It invades from within. Maria de Sousa (MdS)— I don’t like the word crab [for that purpose]. How do you describe cancer?
“All begins with a tumor, a mass.”
MdS —For this interview, which is very difficult, I have tried to place cancer under a historical perspective, out of respect for people who have cancer and for all of those who will have it a near future. All begins with a tumor, a mass. With scientific development, the first treatment is surgery. We remove it. Then, people realized that, even after being removed, that thing never ends – it comes back. And other treatments are developed: radiation. Later, with the appearance of immunology, people start giving importance to “immune surveillance”. Then, chemotherapy appears. Nowadays, the treatment of a person suffering from cancer may still follows these steps. The treatments are more sophisticated but have remained essentially the same.
“How is cancer different from AIDS?”
MdS — There is some progress, which allows for better prevention and outcome. However, in general, things are not that much better. In general, we still need to tell a friend who is suffering from cancer that there is not much to do. How can the treatment of AIDS have undergone through so much progress in 30 years? How is cancer different from AIDS? It has been 200 years of developments in cancer, but the success rates of cancer treatments are not even comparable to those of treatments for AIDS.
9
AIDS in 1980 represented death. And 30 years later, it is a chronic disease. MSS — Controllable. Even though many cancer types are curable and some can be considered chronic diseases, the stigma of cancer as a lethal disease still prevails. “There is something terrible about cancer.”
MdS — It is no a stigma. It is the truth. MSS —I agreed with Maria. There is something terrible about cancer. We all have friends who died of cancer, and friends who have or friends will have cancer. Even ourselves. That is difficult… MdS — The interview itself [is difficult]. Immensely.
“...cancer is a living creature within ourselves, a creature that does not respect any boundaries.”
MSS — I understand that you don’t like the word crab [to represent cancer] because it is dated. However, there is something about it that is still true: cancer is a living creature within ourselves, a creature that does not respect any boundaries. It is because of this lack of respect, that cancer shows up in different places. It is able to “reproduce” itself at distance. That is the danger! Over 50% part of people suffering from the majority of cancers will not die of it. But we know that [some] may die. Is it a threat? MSS — Yes. It is a threat. The magnitude of this threat is no longer supported by numbers [e.g.,mortality rates], but it still scares us.
“How have things evolved so much and we still do not know the frontiers [of cancer]? We know so much, so much. But there is something missing and it is missing because of the way we conduct research, the way science works.”
MdS — The difference between us [MSS and me] is that I, as a basic biology researcher, feel guilty. How have things evolved so much and we still do not know the frontiers [of cancer]? We know so much, so much. But there is something missing and it is missing because of the way we conduct research, the way science works. Let’s look at AIDS again. People suffering from AIDS contributed to the advances in the AIDS research. If AIDS were a disease confined to Africa like malaria, if it did not affect people living in San Francisco, the related research probably would not have evolved so much. Are you talking about scientific progress? MdS — I am talking about the importance that people, the patients themselves, participate in research. I was in New York in the 80s and back then young doctors had never seen people die that way. That scenario has 10
prompted people suffering from AIDS to participate in research in an extraordinary manner. All a person who has cancer wants is to be treated. Cancer patients do not mobilize themselves as much as AIDS patients.
“Immunologists think cancer will be cured by Immunology. Geneticists believe that the cure will come from Genetics. The problem is that there are not institutions that prompts Immunologists to speak with Geneticists.”
MSS — That is true. Despite of everything, in AIDS, there is an external agent. In cancer, the trigger may be external, which happens often, but is almost never a virus. We are discussing a crucial question: Why have we evolved so little? MdS — The knowledge has expanded. MSS — We improved in terms of knowledge but not in terms of treatment efficacy. But that is not enough. MSS — It has not been enough. MdS — Immunologists think cancer will be cured by Immunology. Geneticists believe that the cure will come from Genetics. The problem is that there are not institutions that prompt Immunologists to speak with Geneticists. MSS — It makes sense. There is an element distinguishing us. Maria is a real scientist; I am a pathologist, a medical doctor. Cancer is a sort of price that we need to pay to keep our species alive.
“Cancer is a sort of price that we need to pay to keep our species alive.”
In your book Gene, Célula, Ciência, Homem: Malign neoplasias, you also designated cancer as a “price to pay to keep our capacity to evolve”. That’s terrible! MSS — [The price to pay for] keeping a species that, on top of everything, has extended life duration. Moreover, the members of this species have increased sun exposure, have gained weight... smoke, and take immunosuppressive drugs. Our problem is that cancer is not a cause; it’s a development. The development is ours, is us. And this development comes with such an extensive genetic instability that all this [research] progress is, as Maria says, only partial. Many people think that, when we know more about the genes, epigenes, and metagenes, when we have the complete genetic profile for each person, we will be able to treat each person individually by identifying, for example, genetic targets. But the more therapeutic targets, the higher toxicity.
11
In essence, we are always targeting something that is part of ourselves. MSS — The targets are part of ourselves. I am very skeptical about our ability to treat cancers that are already fully developed. I am much more inclined to believe that we will control the disease. MdS — That is the part that has evolved the most. Does it include early diagnosis of cancer? “I am much more inclined to believe that we will control the disease.”
“We all are going to have at least one kind of cancer, but it will happen so late in life that it will not cause any problem.”
MSS — Early diagnosed cancers are treated with surgery. A surgery may cure cancer if we are lucky and the cancer has not extended beyond its boundaries, if there are no metastases. As we become older, our exposure to environmental risk factors increases and the system of repairing genetic errors becomes more prone to fail; consequently, we will have a greater frequency of cancers. In Cancro [Cancer], you write: “Besides a great number of people suffering from early cancer who are treated successfully and are cured of the disease, there are more and more cancer cases in which the treatment does not allow to cure the disease but rather to control it.[…] Our situation is not much different from that in other European countries: one out of three Portuguese people will be diagnosed of cancer. The good news is that half of those will survive the disease.” MSS — We all are going to have at least one kind of cancer, but it will happen so late in life that it will not cause any problem. We will die with our cancers. We are talking of two separate kinds of cancer. A kind of cancer that is lethal to a young adult, a teenager or a child. And a kind of cancer that older people may have if they extend their lives to 90, 100 or 110 years of age; those people will inexorably suffer from two, three or five cancers.
“historically, the immune system is thought to protect us, people think those immune cells are there to kill the tumor.”
Before we speak about cancer as a chronic disease, let us focus on immunology. MSS — We thought the immune system was to defend us against something from outside. MdS — Immune cells show up in an earlier phase of the tumor. Because historically, the immune system is thought to protect us, people think those immune cells are there to kill the tumor. Interestingly, Manuel Sobrinho is the first person saying that maybe that’s not always the case.
12
MSS — In thyroid cancer, some lymphocytes are not there to kill cancer cells; instead, they provide cancer cells with growth factors. Could you explain that?
“Educational programs are becoming highly focused: the student graduates from a program knowing only a given thing.”
MSS — [During my PhD studies] I knew that thyroid cancers grew little, divided little, but were aggressive. At the time, I started seeing autophagic cells (cells eating themselves) under electron microscopy. And, like a dummy, I wrote on my thesis: “... an autophagic cell is almost ready to die.” I didn’t realize that autophagy is a surviving mechanism of the cell. A malign cell undergoes partial autophagy so that it can use up its own cytoplasmic “food” to survive. By becoming smaller, a cell spends less energy. MdS — I would like to make sure that people who read this interview understand what Manuel has just illustrated: a person, alone, can see things and may believe that he/she will be able to reach a solution for a given problem. But no one does it on their own. It is necessary to incorporate knowledge from surgery, chemotherapy, immunology… He says, “ I was a dummy”. He wasn’t a dummy. At the time, he only knew that. That’s what people knew then. Educational programs are becoming highly focused: the student graduates from a program knowing only a given thing. Education is too sectorial and does not promote a cross-sectional approach. MSS — It is worse than sectorial. It is self sustained. A person is rewarded for being sectorial.
“Let’s go back to AIDS. Imagine what we would have lost if the minister for economy had told that knowing about T4 cells was not useful, because that knowledge did not yield any money.”
MdS — Education is financed to be sectorial. Economy, governments, and not only in Portugal, want “science that is useful for…”. Let’s go back to AIDS. Imagine what we would have lost if the minister for economy had told that knowing about T4 cells was not useful, because that knowledge did not yield any money. Scientists and educators are the main responsible [for progress], but the society we are all part of has also a role. We need to have educated patients. AIDS is a great example of how knowledge, science and society were integrated. MSS — All Maria is saying makes sense. I was looking at those trees. I find them intriguing because they are still. But their crowns move, almost dream, have the capacity to adapt to different weather conditions. Why trees? MSS — Trees stay still in spring and summer. They resist to lack of water, 13
to extreme heat. Their cells have features that provide them with surviving capacities. Cancer cells have those features as well. We all develop cancer cells but we get rid of them every day. We have a misfortune of having cancer because things happen in those cells and in their daughter cells… MdS — And in the microenvironment. “[Plant] cells have features that provide them with surviving capacities. Cancer cells have those features as well.”
MSS — Of course. [We have cancer] because [certain] events provide those cells with some sort of growth advantage. Cancer represents those cells’ success, our failure, but their success. When we study cancer cells, it is interesting to find several situations in which those cells show the same resistance mechanisms that plant cells have. Cancer is a multicellular living being, just like ourselves. And that defeats us. MSS — It defeats us because it is more efficient.
“[Cancer] defeats us because it is more efficient.”
MdS — My first reaction is always to feel responsible for the failure our attempts to cure cancer because part of that failure is attributable to the universities. People with mammal cells have a lot to learn from plants. In our educational system, 15-year-old kids need to decide whether they are to study Sciences or Humanities. Some will grow without knowing what a gene is, what a cell is. Some will grow without knowing who Spinoza was. Botany was never taught in Med Schools… MSS — But it should.
“My first reaction is always to feel responsible for the failure our attempts to cure cancer because part of that failure is attributable to the universities.” “Maybe we will understand how to change that environment to favor the host rather than the cancer.”
MdS — Without any doubts. We have something that grows. That grows in an environment. Everyone understands that this environment changes with age; we need to know why it changes. By doing so, maybe we will understand how to change that environment to favor the host rather than the cancer. MSS — Maria is using the word “environment” instead of immunity. She’s right. The idea is that cancer is not a collection of only small cells; it is a rather a tissue of different elements. Let’s go back to plants. What happens if we let a normal cell in a given place to be exposed to sun permanently? It will die. The only way for it to survive would be to escape from that place. Let’s go back now to the fact that cancer does not respect frontiers. Cancer, thanks to its environment and to many other things, is constantly finding new ways of escaping. In 99.9% of the cases, the microenvironment and the immune system destroy the cancer cells if they don’t evade. Well, it is always possible that one of them, suddenly, evades… sheer chance.
14
Is it a matter of luck? A roulette? MSS — People who suffer from cancer are not very lucky. We say tobacco causes cancer; it does, but only in 15% of smokers. God forbid that I start accusing people suffering from cancer, with something like “They were asking for it!” It is stupid.
“The answer is to create freedom. You will never ask different questions if you don’t have the freedom of asking them.”
“To win grants, scientist need to shape themselves into what is wanted.”
Let me go back to the topic of education. In Meu Dito, Meu Escrito, Maria de Sousa speaks about the right to question and to doubt… about how “fresh” a question is. “The most important in the construction of a scientist is never stop listening to the child within oneself.” How do we ask different questions? How do we reach different points of view? It’s a question that probably doesn’t have an answer. MdS — It does have an answer. The answer is to create freedom. You will never ask different questions if you don’t have the freedom of asking them. Schools, the way we are financing research, everything is limiting the way we ask different questions. Research teams who write grants need to write the expected results. No one funds unexpected results anymore. MSS - To win grants, scientist need to shape themselves into what is wanted. And it is not only in the field of cancer, it is everywhere. There is little freedom because [otherwise] there is a high risk of not having results. And the funding agencies want us to present preliminary results –something that is already done. MdS — Something that, if possible, gives money. What’s the role of the pharmaceutical companies?
“The investigation is well formatted. The advisors are biased. The scientific journals are…” “Very biased.”
MSS — That is the other side. The different types of cancer, such as skin, stomach or pancreas, share a lot of things. A pharmaceutical company develops a drug that is efficient for stomach cancer, and then pays scientists to test whether that drug is efficient to treat other cancers, such as the ovary cancer… Does it happen often? Does it give any results? MSS — Permanently. We designated that strategy as “ Me too!” It renders some results, but the questions are not very smart, are not of the kind of questions Maria was talking – a curious and cross-sectional question. The investigation is well formatted. The advisors are biased. The scientific journals are… MdS — Very biased. 15
“Besides hereditary cancers, which represent less than 5% of cancer, there are families with an elevated prevalence of cancers (around 10%)” Sobrinho Simões, in his book about cancer. There is a myth that the genetic susceptibility weighs a lot in the equation. However, the hereditary factors play a role only in 5% or 10% of the cases.
“In Africa, people do not live enough to suffer the influence of environmental factors that play a role in cancer here in Europe, where people live until they are 80 or 90 years old. “
MSS — We have most progress in familial cancer, in which the gene increases the risk of cancer, because there is causality in those cases. These are from 5 to 10% of the cases, 10% in breast cancer, 10% in colon and rectum cancer, less than that in gastric cancer. We do not know very well what goes on in prostate or lung cancer. In lung cancer, the most important risk factor is smoking. Those 5 or 10% are not independent of the environment. Those 5 or 10% are not true in Africa. Why? MSS — In Africa, people do not live long enough to suffer the influence of environmental factors that play a role in cancer here in Europe, where people live until they are 80 or 90 years old. As people in Africa tend to die younger, the role of genetic factors is greater [than here]. Against the statistics, we think that, if no one suffers from cancer in our family, we are less likely to be suffer from cancer. MSS — There was never a case of cancer in my family. We had cases of strokes and diabetes. And I, who researched on cancer, never realized the threat that cancer poses to myself and to the people I love until my father died of cancer.
“...we were entering something that penetrates everything: the world of expectations, the world of fear that distorts reality.”
You realized it when the threat was closer to you. It no longer was an abstraction. MSS — [I realized that] we were entering something that penetrates everything: the world of expectations, the world of fear that distorts reality. Until my father’s death, I had never realized the risk because no one in my family had suffered from cancer until then. Your speech, your questions, your actions, even while scientists, are affected by the fact that you have friends and relatives who suffer from cancer. An affective dimension is present throughout this interview and breaks out like a ghost. Because those are people we love. Because we all can die of cancer. It changes everything.
16
MdS — Completely. Scientists have a social responsibility and an ethical responsibility, as well. We have an extra responsibility in relation to knowledge and ignorance. MSS — The cancer I study, the thyroid cancer, almost does not kill any one. MdS — It doesn’t kill if…
Research on thyroid cancer is less rewarding in economic terms because the cancer is less lethal.
MSS — We have 30-year survival rates of 95%. In a phase of my life, I was interested in gastric cancer. Then I dropped that interest. More competent people were interested in that cancer. At that time, I realized that I felt much less at ease in gastric cancer because the patients died. I went back to thyroid cancer. If you want to be successful in cancer research, you must choose cancers with highest mortality rates. That’s where you can assess clearly whether the research is influencing the prognostics or not. In thyroid cancer, it’s not possible to have that kind of assessment or at least to the same extent. I give only good news, even when I say, “You have cancer”, I add, “We’ll treat it”. Are the resources, the research choices made better in some types of cancers than in others? Or does the attention given to a certain cancer vary depending on where we are?
“The research is biased towards cancers that are most prevalent in Western society”
MSS — Research on thyroid cancer is less rewarding in economic terms because the cancer is less lethal. The research is biased towards cancers that are most prevalent in Western society, such as pancreatic cancer or brain tumors. There is not much research about the cervical cancer because this type of cancer is most prevalent in Africa. This is very complex, because our way of regarding cancer depends not only on our personal experiences but also on the place where we are.
“Manuel Sobrinho Simões has made great and pioneer contributions to our knowledge about thyroid cancer.”
MdS — Manuel Sobrinho Simões has made great and pioneer contributions to our knowledge about thyroid cancer. People do not know that. His research is not going to give much money to pharmaceutical companies related to chemotherapy. Now, ask us what happened in Chernobyl. IPATIMUP, created and directed by Sobrinho Simões, worked with victims from Chernobyl during years. MSS — The reactor blew up and threw all that radioactive iodide into the air, the same radioactive iodide that, in very high dose, is used to treat cancer cells but, in low doses, may cause cancer. And it did cause cancer. Mostly in children who drank milk. We are one of the six research institutes that were chosen to study this. There was high frequency of thyroid cancer in Byelorussia, because the wind would come from Ukraine to Byelorussia. Five or six people died, although there were hundreds of people developed cancer. We treated them. Maria’s point is that we treated because we had 17
knowledge that allowed for the treatment to be developed. MdS — Something that is generally not considered by ministers for economy. MSS — We identified a cause. It was the radioactive iodide. In the cervical cancer, the cause is Human Papilloma Virus, HPV, and there is a vaccine.
“it’s important that we speak about cancers rather than the cancer.”
The same is bound to happen in gastric cancer: we should find a vaccine against Helicobacter pylori. Gastric cancer is associated with highest mortality in Portugal, in both genders. You defend in your book that the high rates of incidence are caused by environment factors rather than genetic factors. MSS — Exactly. MdS — In the thyroid cancer, we know the cause but we do not know why there is so much variation across tissues. Why? People have just started asking this question. As a Portuguese scientist in Portugal, in this phase of my live, in which I am not longer working in a laboratory, I’m interested in knowing whether Portugal (with people like Sobrinho and all the young people in his institute) can contribute to answering that question.
“Even in the case of breast cancer, there is not a single kind of breast cancer.”
MSS — That takes a lot of time. And as time goes by, the number of potential patients increase. The number of people who do not die early will continue to increase. If they don’t die of stroke or heart infarction, they will develop neurodegenerative diseases or cancer. Maria de Sousa brought an excerpt from New York Times in January in 2014. In brief, the article says that we all are going to have cancer in a near future. It is frightening but it’s something we need to face. MdS — I spoke with someone who does research on cancer. He thinks it’s important that we speak about cancers rather than the cancer. There isn’t cancer. There are cancers. Suffering from pancreatic cancer is different from suffering from breast cancer. MSS — Very different. MdS — Even in the case of breast cancer, there is not a single kind of breast cancer. Cancers are, themselves, very different. And the hosts, the women, are also different. And then, it is important to have a second opinion….
18
MSS — I am totally in favor of that. Do people ask often for a second opinion in Portugal? MdS — No. For cultural reasons? Because that may hurt the doctor’s sensibility?
“Patients tend to feel uncomfortable with asking for a second opinion. Not especially for cancer, but for everything. It is a great problem in our society: we are not used to confronting.”
MSS — It is true. Patients tend to feel uncomfortable with asking for a second opinion. Not especially for cancer, but for everything. It is a great problem in our society: we are not used to confronting. MdS — That has to do with patients’ education. Knowledge is the most important thing. Portuguese patients should not be afraid of asking a second opinion. MSS — I want to say that I agree that there is not a single cancer. There are cancers. The word cancer is not very appropriate. MdS — That’s the reason I don’t like the word crab [ as symbol of cancer]. MSS — Things are probably going to turn out to be fine for a person who suffers from thyroid cancer or testicular cancer. However, things are probably going to be bad for someone who suffers from a brain tumor or pancreatic cancer. But even in the case of pancreatic cancers, there are an increasing number of cases with good prognosis.
“We need to to know the type of cancer and the stage it was diagnosed.”
So, it’s not enough to say pancreatic cancer. We need to know the type of cancer and its relationship with the host? MSS — We need to know the type of cancer and the stage it was diagnosed. [The treatment of ] pancreatic cancer may be successful in those cases associated with repeated bouts of jaundice without biliary lithiasis. Jaundice happens when bile doesn’t flow properly and is generally caused by biliary lithiasis. A patient who has bouts of jaundice without biliary lithiasis is likely to have pancreatic cancer blocking the regular bile flow. When a patient is diagnosed with this type of cancer early, that patient may be cured of it. It is essential that we have the right knowledge and we surveil ourselves and our health status. What exactly can we do? MSS — The first thing is prevention. We shouldn’t smoke, gain too much 19
weight, or drink too much. We should avoid sun exposure for too long or during the “bad” hours. Those are things we know we need to avoid. We need to be vaccinated. If you are not vaccinated for HBV and for HPV, you are more likely to develop liver and cervical infections respectively. As a parenthesis, let me talk about a different topic. The trend – it’s often regarded as a trend- of not vaccinating children… MdS — It’s criminal. “[Not vaccinating children] is criminal.”
“if we interrupt the vaccination programs, we interrupt a great achievement of our societies”
MSS — People don’t vaccinate children because vaccination is associated with a risk, which is minimal, but real, of having certain immunological diseases. That risk is much smaller than the risk of having the disease for which the vaccine is protective. Most of all, if we interrupt the vaccination programs, we interrupt a great achievement of our societies, just like other advances related to access to potable water and hospital childbirth. There are people who may prefer to give birth in a stream of water. “It’s very natural.” [They say.] It is nonsense, completely totally inept, pre-scientific and criminal for themselves and for society. MdS — It is frightening! It’s bewildering! MSS — Let’s imagine a case in which a mother delivers at home in poor condition and her child develops cerebral palsy. This is costly not only for the parents and for the child, but also for the society. We all pay for a case like that.
“People have access to a lot of information, but they’re not educated. If we value our children, our friends, we need to take care of our lives.”
We were just talking about surveillance and about the importance of screening. Cancer is increasingly more visible. And people talk more about it. Not many years ago, we would say that someone died of “prolonged disease” rather than of cancer. On the other hand, we hear more and more news about cancer, but we secretly hope that it doesn’t touch us. [We don’t want to get too close to it] and we end up not being very vigilant. How to reconcile all this? MdS — All that relates to poor education. Poor scientific education. People have access to a lot of information, but they’re not educated. If we value our children, our friends, we need to take care of our lives. I live in Passeio das Virtudes in Porto; there, the trees know when it’s spring and when it’s winter. No matter whether it’s raining or it’s sunny, they’re not going anywhere, but they’re probably going to outlive us. If we want to be alive, we need to be careful. And it’s exactly in the field of prevention that the most impressive advances have been made.
20
MSS — The problem is not only cancer. The problem includes hypertension, stroke… Cardiovascular diseases kill the most in Portugal. Cancer comes second. The country’s health costs with the latter are smaller than those with the former. MSS — As a society, we have difficulty in incorporating the risk. We all have that difficulty, I do too. Compared with people in Mediterranean countries, people in Northern European countries tend to perceive the risk better and to use that perception to change their behavior. This difference has to do with the lack of scientific culture and literacy as well as with religion in Mediterranean countries. “Compared with people in Mediterranean countries, people in Northern European countries tend to perceive the risk better and to use that perception to change their behavior” “My grandmother used to give us a bottle of holly water from Fatima, which we stored in the restroom, under the sink.”
What role does religion play in all this? MSS — Among protestants, there is an idea of revenge (“you “pay” for your misdeed”). The person and social responsibility is more to the point. We [Catholics] have the idea that God protects us. If we regret of our misdeeds, all is forgiven and zeroed out. My grandmother used to give us a bottle of holly water from Fatima, which we stored in the restroom, under the sink. Whenever we had a wound, my mother would clean it with that water [laughter]. My mother is a very smart person and my father was a doctor and a scientist. I’m glad that you talk about this. We normally have the idea that believing is synonym with ignorance and that important people do not perform rituals like those.
“I have been observing something horrible in Norway. Norwegians get angry at immigrates who are fat.”
MSS — It’s cultural. But those who perform those rituals are not very careful in not smoking because they believe that if anything ought to go wrong, it goes and God protects us. We have an extreme responsibility for our behaviors and we were not trained to take that responsibility. In any case, the system begins as punitive. Blaming someone [for being ill] is indecent because developing cancer is a misfortune. What is it like in Northern European countries, with which you continue to collaborate after conducting postdoctoral studies there? MSS — I have been observing something horrible in Norway. Norwegians get angry at immigrates who are fat. Those immigrants use the National Health System more than Norwegian citizens. We start hearing people say that we should weigh immigrants when they arrive. And measure their ab21
dominal waist circumference. MdS — Is that legal? MSS — It’s not in the law, but it’s happening. That is a social punishment. But there is also a different punition when someone asks “Why me?” trying to convey various kinds of perplexity and guilt. Why did have such misfortune? What did I do to deserve this? “We have some prejudice against some diseases. It is more than seeing the disease as a punition, but feeling that a person suffering from that disease is frail.”
MdS — The “why me” is very common. MSS — It’s true. But that does not happen only in relation to cancer. It happens in relation to any serious disease. In Brazil, people didn’t use to speak about leprosy. “Leprosy? Here, we don’t talk about leprosy. We call it Hanseniasis.” Hansen’s disease because Hansen was the first to describe it. We have some prejudice against some diseases. It is more than seeing the disease as a punition, but feeling that a person suffering from that disease is frail. Note that, being myself a cancer specialist, I dread to have cancer. I’m scared. I know that most of them are controllable, but I know that 30% or 40% are not. And if I have the misfortune to get one of those… Going back to the New York Times piece: why does it seem that we all will end up suffering from cancer? MSS — Now the prevalence is one out of three. Thirty years from now, in developed countries, for example in the US, it will be one out of two.
“Although the incidence is increasing, we have made advances in terms of prevention, early diagnosis and treatment. It is horrible to say this, but we are dying of infections.”
“We, people of the European Union and of the North America, in 2030, will be living in a situation characterized of high incidence of cancer in a much older population, and of high frequencies of neurodegenerative diseases”. You wrote in “O Cancro” [ The Cancer]. In a different part of the book, you compare this situation to plagues in the Middle Ages, tuberculosis in the XVIII and XIX centuries, cardiovascular diseases in the XX century. Should we regard cancer as an epidemic affecting everyone in the XXI century? MSS — It is not going to kill us. It’s very important that people realize that. In places, in which the prevalence is one out of three, or one out of two, people are dying less of cancer. Although the incidence is increasing, we have made advances in terms of prevention, early diagnosis and treatment. It is horrible to say this, but we are dying of infections.
22
Infections?
“[AD patients] are dying of respiratory infections, heart failure, systemic failures, urinary infections.”
MSS — We have an important problem with an increase of tuberculosis incidence in Europe. In part, because treatment have created resistances, in part because we no longer have dispensaries. In part, because economically, there are more poor people, and there more migratory fluxes, which didn’t exist before. We now have Alzheimer’s Disease (AD) and cancers, but elderly people in the US are not dying of AD – which doesn’t kill directly- or of cancers, because they have small and manageable cancers. They are dying of respiratory infections, heart failure, systemic failures, urinary infections. The system fails. Let’s go back to immunity. Cancer will be much more frequent. Everyone will develop cancer, but will die of other diseases. We need to learn to feel less fear? We need to prevent it so that it is diagnosed and managed earlier? MSS — Younger adults should be careful. People older than 80 years old need to pay some attention, but shouldn’t be too worried that they will develop cancer. Will it be a chronic disease just like all other chronic diseases, with which we lean how to live? MSS — Exactly. Just like diabetes. And we will need to avoid over-diagnosing.
“Vigilance needs to be smart; it cannot be a brainless series of steps.”
Vigilance, yes, but not hypervigilance. MSS — The word cancer comprises several different realities. The vigilance needs to be smart; it cannot be a brainless series of steps. South Korea and Japan have same incidence rate of thyroid cancer, but there is a difference between these two countries. In South Korea, people have decided to perform needle aspiration for any nodule, so that they can see if it’s cancer and overtreat it. In Japan, it’s the opposite. Whenever a nodule is less than 1cm, they don’t do anything. They monitor it every year to see if it grows or not. Thyroid cancer is the most frequent neoplasia in women in South Korea. In Portugal, it’s the fifth. Are the results, after all, the same? Do they have the same mortality rate? MSS — No one dies of thyroid cancer. Japanese people spend much less money, and Japanese women don’t dread to have thyroid cancer. This is 23
true for prostate cancer in the men, and breast cancer in women. Women have several microcancers that are to be treated. If we start treating them, we end up ruining… MdS — The variation across organs is very important. It’s something only now people start to value. MSS — That doesn’t negate that a person who is 39 years and develops a large thyroid cancer needs treatment. The same can be said for prostate cancer in 56 or 60 year-old men. Or for breast cancer in 45-year old women. “The education of the patients, I insist, is extraordinarily important.”
MdS — See how important this conversation is. If people don’t understand that they may have thyroid cancer — people in South Korea – and that is harmless… The education of the patients, I insist, is extraordinarily important. And so is the fact that patients can teach their doctors, which is something that almost no one thinks about in Portugal. What do you mean? MdS — Education in general, the education of a patient, in particular, and asking for a second opinion are very important. People are afraid of dying. If they hear that they have thyroid cancer, they want to be treated when they don’t need to.
“In his PhD studies, which [according to him] were not very useful because thyroid cancer is not important, he found thyroid cancer in 500 autopsies. This work would never be funded, but it is this work that leads him to be invited to go to Norway, that leads people seek him for help after Chernobyl”
I come back to the thyroid gland. I want to speak about hope. If there were a single kind of cancer, and if that were a crab, no one suffering from thyroid cancer would survive. As Manuel said, no one is interested in thyroid cancer because it doesn’t kill. I say that thyroid is very interesting because something happens in that kind of cancer that prevents the crab from growing. Let’s situate Prof. Sobrinho Simões. What was the topic of your PhD thesis? How many autopsies did you perform? MSS — Around 500. MdS — In his PhD studies, which [according to him] were not very useful because thyroid cancer is not important, he found thyroid cancer in 500 autopsies. This work would never be funded, but it is this work that leads him to be invited to go to Norway, that leads people seek him for help after Chernobyl. And again, we are talking about the fact that research questions are limited by funding, by the expected results. If we define a certain direction, we’re going in that direction, the path is drawn. MdS — Of course there is hope, but we need to be courageous to ask dif24
ferent questions, and do things that are not going to be funded. In a society scientifically educated, there must be freedom and room for kids – like Manuel was – to do things that seem useless. History teaches us that nothing is useless as long as it is well done. Words have a certain burden. The word tumor, the word cancer… MdS — Are frightening. And that’s why it’s so important to speak about cancers. That way, people understand that the meaning may be different. MSS — Many people defend that these micro-cancers should not be called cancers, but instead are called IDLE, “indolent lesions of epithelial origin”. There’s a saying that goes “devil works with idle fingers”. “Indolent”. This affects even health insurance. A woman who develops a microcancer does not have access to the same kind of health insurance that a woman who was not diagnosed a microcancer has.
“micro-cancers should not be called cancers, but instead are called IDLE, indolent lesions of epithelial origin”
In practical terms, what do people need to do every year after a certain age. In the case of women, mammography? Pap test? MSS — It is not necessarily every year. It varies. It depends on the age, on the risk, on previous assessments. Depending on the results of the previous colonoscopies and on familial history, a colonoscopy is recommended to be performed every 2 years or every 5 years. MdS — But it should be done regularly after 50 years of age. MSS — The value of mammography is not debatable. What is debatable is when to begin that screening. And if it’s every year or every other year? MSS — Exactly. Again, family history is important. And sensibility, which is more important than having strict rules. For example, it is important to monitor a person who starts experiencing bowel transit changes or who has a mole that has changed its appearance. Prevention works fine in terms of colon, breast and cervical cancers.
25
What about the stomach cancer? Is there a way of screening it? MSS — No. There is no screening for brain tumors, pancreas, liver, lung cancers. You can perform a lung X-ray every year, but that increases the radiation a person accumulates in different organs. And we know that, when a lung nodule is detected by X-ray, unfortunately, it is already too late for it to be removed without any problems. The sensitivity of the X-ray is not enough. Now, people start to perform spiral CT, which is much more efficient. But the problem is that the CT increases the level of radiation. In terms of cost/benefit, this is complicated. “It is a strange disease. The host must be deaf so that he doesn’t realize that danger.”
This is such a sensitive and complex topic, can we give our readers some guidelines? MdS — What came out of this conversation is that prevention is very important and that having a tumor is not a death sentence. MSS — In the majority of the cases, it isn’t. And it will be less and less of a sentence. Cancer incidence rates have increased exponentially in the US but the mortality rates are diminishing. Mortality rates are below 40%.
“What we know is the smallest part of what we do not know”
MdS — It is important that people feel that. Because people are not ready to die. Let’s look at a cell, which has such a strangely beautiful organization, how can a cell grow in such a way that takes over the entire human being? It is a strange disease. The host must be deaf so that he doesn’t realize that danger. It is understanble that the immune system will help. But the immune system started as system to defend what comes from the outside. And a tumor that is so similar, so much alike the host, only rarely will be recognized as a danger by the immune system. Let me remind Garcia D’Orta, as I cite in Meu Dito, Meu Escrito: “What we know is the smallest part of what we do not know.” ***
26
ATG: a City of Knowledge. Let’s take another look at a few of its citizens and some of its knowlegde published since our last issue!
27
City Of Knowledge Part I. Citizens Filipa Ferreira PEDRO CARVALHO GABBA 3th edition, class 1999 EP Abraham Professor of Cell Biology, University of Oxford GABBA 3rd edition, class 1999
What did you study during your PhD?
“During my PhD I studied how microtubule dynamics is modulated by microtubule binding proteins.”
During my PhD I studied how microtubule dynamics is modulated by microtubule binding proteins. I focused on particular class of proteins, the +TIPs, that accumulate specifically at the most dynamic microtubule ends, the so called “+-ends”. While the precise mechanisms by which +TIPs affect the dynamic properties of MTs is still a hot topic in cell biology, it is now widely accepted that these MT regulators play key roles in a number of fundamental cellular processes such as chromosome segregation in mitosis or spindle positioning during asymmetric cell division. What made you so fascinated about yeast as a model organism?
“The way I ended up working with yeast was completely fortuitous.”
During my first year at GABBA, I settled on the idea of carrying my thesis work on mitosis and/or cytoskeletal dynamics. However, the way I ended up working with yeast was completely fortuitous. After looking at the beautiful mitotic figures in fly, newt or mammalian cells, I should say that in the early days of my PhD at David Pellman’s lab, I was not impressed. I was almost disappointed by what yeast had to show. With time, however, I learned how powerful and awesome yeast cells can be! So the fascination for yeast came a bit later, like in the advert from Pessoa “primeiro estranha-se depois entranha-se”. 28
What did you consider before you transitioned to a postdoctoral position? “My postdoc position should be a big change, in terms of the research topic, the technical approaches or model system to use”
“extremely diverse backgrounds and training- a nice mix of cell biologists, biochemists as well as hard core structural biologists. Thus, our morning coffees, lunchtime or journal clubs were interesting and more importantly, hugely instructive.”
“We loved our time in the US but our daughter was almost in school age so it was a good moment to move back and be closer to the family.”
If there were any doubts, they all disappeared. During the PhD, I realized that my major interest was really understanding how cells work. So I was looking for a cell biology lab but was not sure about the topic. Among all the advice I received from my PhD mentor, a key advice was that my postdoc position should be a big change, in terms of the research topic, the technical approaches, or the model system to use. I took his words seriously and considered 4-5 labs in very different areas that used a variety of model organisms from flies to frogs, mice and mammalian cells. At the end, I kept working with yeast but on a radically different topic- biogenesis and quality control of membrane and secreted proteins. I am not sure if I considered many other factors when looking for a postdoc lab. However, in retrospect there were a few other aspects that turned out to be quite important for my training at Tom Rapoport’s lab. Without being huge, the lab was of a decent size (around 15 people, mostly postdocs). More importantly, these people had extremely diverse backgrounds and training- a nice mix of cell biologists, biochemists as well as hard core structural biologists. Thus, our morning coffees, lunchtime or journal clubs were interesting and more importantly, hugely instructive. Another important thing was the fact that the lab was well-funded so people were not afraid of failure and always tried to address ambitious, fundamental questions. You were in the U.S. for both your PhD and postdoc. When you were applying for Group Leader positions were you specifically committed to return to Europe? After 10 years in the US, my wife and I decided to return to Europe. We loved our time in the US but our daughter was almost in school age so it was a good moment to move back and be closer to the family. The funding situation in the US was also pretty grim compared to Europe. So, even considering that we landed in Barcelona right when the financial crisis hit Spain really badly, I believe we did the right thing. Now I just moved to Oxford a month after the UK referendum that voted for the Brexit… Maybe our history repeating itself! You have been quite successful running your research group for the past 6 years. What were the hardest things you faced during this new stage of your career? The CRG (Center for Genomic Regulation) is a great place to start as a group leader as the institute offers very nice resources. Also, you are free from administrative or teaching obligations which leaves plenty of time to 29
focus on research. Even if these were quite exciting times, the beginning also brought a lot of anxiety. In my case, this lasted until we had our first great results. At that time, I was confident things would work out, that we were in safe territory. Overall, the hardest thing I had to deal with was in managing a highly heterogeneous group of people- I clearly was not prepared to do it. “Even if these were quite exciting times, the beginning also brought a lot of anxiety.”
“I should highlight the role played by Maria de Sousa during this first year. Her mentorship helped me mature and equipped me for the challenges I faced in Boston at the start of my thesis work.”
“On a more personal level, I met my wife at the GABBA program. Cristina is also from the 1999 class and we moved together to Boston to do our PhDs.”
In what way did the GABBA PhD affect your career? I was on my way to Canada with a PhD fellowship from the FCT to do my PhD at the University of Waterloo. When I heard that I had been selected for the GABBA program I did not think twice. The ethos of the program with a preparatory year in Portugal before sending people abroad really appealed to me. This initial year was very useful in providing a panoramic view of a number of research areas that were largely unknown to me. Also I should highlight the role played by Maria de Sousa during this first year. Her mentorship helped me mature and equipped me for the challenges I faced in Boston at the start of my thesis work. On a more personal level, I met my wife at the GABBA program. Cristina is also from the 1999 class and we moved together to Boston to do our PhDs. So it is not an overstatement to say that the GABBA program literally changed my life! Favorite Sunday activity: Day out with the kids Dream vacation: Right now I am thinking of a RV road trip with the kids through national parks in the US. Favorite non-Portuguese cuisine: Catalan, the best surrogate Portuguese cuisine. Sport: Running (preferably long distances). TV show that you binge watched recently: Borgen was my last addiction How do you commute? Bike. Android or iOS: iOS. Pipet tip box usage method (in order, the ones in same area or random): Definitely in very precise order. Friday night drink: Any that keeps me awake.
30
Sílvia Castro GABBA 5th edition, class 2001 Executive Director, MIT Portugal
“I did my PhD at University College London where I studied developmental neurobiology.”
“I did pursue a postdoc after graduation but in a different area, science communications”
What did you study during your PhD and what were the most useful skills you gained during this period for the next steps? I did my PhD at University College London where I studied developmental neurobiology. In vertebrates, cell migration is an essential process for the establishment of a fully functional central nervous system. Its functionality depends not only on the correct specification of each cell type but also on the ability of these cells to achieve their correct position. I used different approaches to address the issues of cell migration and specification in the brain using zebrafish as an animal model. One major contribution to my career came from UCL itself. There, PhD students need to complete coursework in areas not related to their research. I took a few of these courses and, thanks to them, I developed an interested in pursuing other career choices. When and how did you decide you weren’t pursuing a postdoc when you graduate? I did pursue a postdoc after graduation but in a different area, science communications. At the time, you could apply for a FCT postdoc fellowship in Promotion and Administration of Science and Technology - Promoção e Administração de Ciência e Tecnologia (PACT). I developed an interest in this area while I was still in London and by the time I finished my graduation a new scicomm office was opening at IGC with Ana Godinho.
31
“I started as media officer at IGC.” “I applied to be MIT Portugal Program’s director of communications.”
“My main functions [as Executive Director at MIT Portugal Program] are to implement MIT Portugal Program’s strategic objectives and the promotion of the interaction between the program’s stakeholders including industrial and academic partners.”
“I still remember of being mesmerized by Rui Costa and Fernado Casares during my first [GABBA] year.”
You shifted from the bench to Science Communication and now to an Executive Director position. How did you prepare and how hard were these transitions? I have to say it was a natural process. I started as media officer at IGC with a FCT postdoc fellowship to study the interaction between media and journalists; midway through I started to study the use of social media for scicomm. By the end of my first 3 years of postdoc, and already with the renewal for more 3 years, I applied to be MIT Portugal Program’s director of communications. There was an increase of responsibility but also the opportunity to learn about a new field, engineering, and with the plus of being in international context. After two years, I was also managing four PhD programs and three executive masters of the MIT Portugal Program. I had then a very good overview and understanding of all the components of the partnership, which conducted me to the position I have now. How is a day as ‘Executive Director at MIT Portugal Program’? The MIT Portugal Program is an international partnership involving MIT, universities and industry in Portugal. The goal of the initiative is to develop world-class education and research programs in critical areas of contemporary society. So my main functions are to implement MIT Portugal Program’s strategic objectives and the promotion of the interaction between the program’s stakeholders including industrial and academic partners. These are key functions to support the program’s directors, Pedro Arezes and Bruce Tidor, to prepare a competitive proposal allowing the program to progress into a third phase in 2018. Because the coordination of the program at MIT is in a different time zone than the national coordination here in Portugal, Skype calls tend to be in the afternoons. I also supervise the communication strategy of the program and the management of educational programs, so part of my day is spent developing strategies and accessing processes with coordinators of these areas. In what way did the GABBA PhD affect your career? First of all, it gave me an excellent overview of several areas of research and to interact with great scientists of different institutions. I still remember being mesmerized by Rui Costa and Fernado Casares during my first academic year - I think I chose to study Developmental Neurosciences because of them. GABBA allowed me to pursue a PhD in a field that was different from my initial training in Biochemistry and the opportunity to do it at UCL, where everything began to change in direction to where I am now.
32
Favorite Sunday activity: Spending time with my daughter at Gulbenkian or CCB. Dream vacation: Return to Japan soon! Favorite non-Portuguese cuisine: Japanese. Sport: Running/ Swimming ( I miss the cycling to do my first triathlon‌. well, maybe one day). TV show that you binge watched recently: Game of Thrones! How do you commute? By car, unfortuntely is the quickest way. Android or iOS: iOS without a single hesitation. Pipet tip box usage method (in order, the ones in same area or random): Random. Friday night drink: G&T.
***
33
City Of Knowledge Part II. Knowledge Catarina Seabra & Ana Rita Araujo
B
ecause this issue is dedicated to cancer, we give special attention to the publications from the field of Cancer Research by the GABBA Community. Patricia Oliveira, GABBA 10th, is now a postdoctoral fellow in the Expression Regulation in Cancer Lab led by Carla Oliveira, GABBA 2nd at i3S, Porto, Portugal.
Oliveira, P., Carvalho, J., Rocha, S., Azevedo, M., Reis, I., Camilo, V., … Oliveira, C. (2016). Dies1/ VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation. Scientific Reports, 6, 34860. http:// doi.org/10.1038/srep34860
The Expression Regulation in Cancer Lab’s main focus is to disclose germline and somatic regulatory mechanisms and molecular circuitries, acting to increase gastric cancer susceptibility, and to confer advantageous features to tumor cells in order to improve gastric cancer diagnosis and patients’ management. 34
Their most recent publication focuses on Dies1, which is involved in cell de/differentiation, inflammation and cancer processes. They analyzed Dies1 expression, its regulation by promoter-methylation and miR-125a5p overexpression, and its association with BMP-pathway downstream-effectors. Their findings place Dies1, a novel player in gastric cancer, with distinct roles within tumor cells and in the tumor-microenvironment. As part of her PhD studies, Joana Nabais, GABBA 16th, has been focusing on the relationship between telomeres maintenance and human disease, both at the Curie Institute (Paris, France) and at the Instituto Gulbenkian de CiĂŞncia (IGC, Lisbon, Portugal).
Vinagre, J., Nabais, J., Pinheiro, J., Batista, R., Oliveira, R. C., Goncalves, A. P., ‌ Soares, P. (2016). TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes. Scientific Reports, 6, 29714. http://doi. org/10.1038/srep29714
Her most recent contribution was published in Scientific Reports. This study reported telomerase promoter (TERTp) mutations in pancreatic endocrine tumors (PETs), particulalry in patients with hereditary syndromes. In addition, their work with PET--derived cell lines suggested that TERTp mutations increase telomerase transcription activity. Andreia Pinho, GABBA 9, joined the Garvan Institute of Medical Research (Australia), where she is focused on providing further insights into the molecular mechanisms underlying the development of pancreatic cancer. More specifically, she aims to uncover the function of novel signalling pathways altered in pancreatic cancer patients, identified through the Australian Pancreatic Cancer Genome Initiative (APGI). Her functional studies intends to determine whether these novel genes have a role in the development or dissemination of the tumour, and consequently could help determine new biomarkers for early detection or new therapeutic targets. 35
Her most recent publication in Oncotarget focusing on the lysine deacetylase Sirtuin 1 opened perspectives for novel targeted therapies in pancreatic cancer. SIRT1 regulates metaplasia in the pancreas, however it was unclear if SIRT1 affected the development of neoplastic lesions and whether metabolic gene expression is altered. Indeed, they confirmed a stimulatory effect of SIRT1 on proliferation and glycolysis gene expression.
Pinho, A. V, Mawson, A., Gill, A., Arshi, M., Warmerdam, M., Giry-Laterriere, M., ‌ Rooman, I. (2016). Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. Oncotarget. http://doi.org/10.18632/oncotarget.11013
JoĂŁo T. Barata, GABBA 1st, is a Group Leader at the Instituto de Medicina Molecular (IMM, Lisbon, Portugal). His research group focuses on different facets of cancer biology. The main emphasis has been on hematological malignancies and especially T-cell acute lymphoblastic leukemia (T-ALL) and also oin studying particular features of normal T-cell biology.
Correia, N. C., Fragoso, R., Carvalho, T., Enguita, F. J., & Barata, J. T. (2016). MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia. Scientific Reports, 6, 31894. http://doi. org/10.1038/srep3189
36
They have been trying to determine whether the oncogenic mechanisms they identified in T-ALL are also present in other leukemias, namely B-cell ALL and chronic lymphocytic leukemia, as well as, more recently, in brain tumors. The latest paper from João’s lab suggested that miR-146b-5p is a functionally relevant microRNA gene in the context of T-ALL. The negative negative regulation of this gene by TAL1, a transcription factor critical for early hematopoiesis, and possibly other oncogenes, contributes to disease progression by modulating leukemia cell motility and disease aggressiveness.
Rui M. Reis, GABBA 1st, is currently a Group Leader at the Life and Health Sciences Research Institute (ICVS, Braga, Portugal). Recently, he has published several papers contributing to unveil the misteries of cancer.
Silva-Oliveira, R. J., Silva, V. A. O., Martinho, O., Cruvinel-Carloni, A., Melendez, M. E., Rosa, M. N., ‌ Reis, R. M. (2016). Cytotoxicity of allitinib, an irreversible anti-EGFR agent, in a large panel of human cancer-derived cell lines: KRAS mutation status as a predictive biomarker. Cellular Oncology (Dordrecht). http://doi.org/10.1007/s13402016-0270-z
The first publication (Silva-Oliveira et al. 2016) was the largest in vitro assessment of allitinib cytotoxicity performed to date. Through this study, they were able to identify cancer types that could potentially benefit from this drug and additionally, their findings suggested that prevalent KRAS mutations constitute potential predictive biomarkers for allitinib response. The second paper (Pinto et al, 2016), featured on the image above, focused on prostate cancer - the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. In this study, they addressed the role of Brachyury in prostate cancer therapy resistance and found that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced prostate cancer patients. 37
Bidinotto, L. T., Torrieri, R., Mackay, A., Almeida, G. C., Viana-Pereira, M., Cruvinel-Carloni, A., … Reis, R. M. (2016). Copy Number Profiling of Brazilian Astrocytomas. G3 (Bethesda, Md.), 6(7), 1867–
In the third paper (Bidinotto et al. 2016), they performed Copy number profiling of 65 astrocytomas of distinct malignant grades of Brazilian origin, and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. They found that the number of genomic alterations increases in accordance with glioma grade and using an extensive integrated analysis, they indicated potentially important genes, not extensively studied in gliomas, that could be further explored to assess their biological and clinical impact in astrocytomas.
Pinto, F., Pertega-Gomes, N., Vizcaino, J. R., Andrade, R. P., Carcano, F. M., & Reis, R. M. (2016). Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer. Oncotarget, 7(20), 28891– 28902. http://doi.org/10.18632/ oncotarget.8499 1878. http://doi. org/10.1534/g3.116.029884
Wolfowicz, I., Baumgarten, S., Voss, P. A., Hambleton, E. A., Voolstra, C. R., Hatta, M., & Guse, A. (2016). Aiptasia sp. larvae as a model to reveal mechanisms of symbiont selection in cnidarians. Scientific Reports, 6, 32366. http://doi.org/10.1038/ srep32366 Lima, A. C., Jung, M., Rusch, J., Usmani, A., Lopes, A., & Conrad, D. F. (2016). Multispecies Purification of Testicular Germ Cells. Biology of Reproduction. http://doi.org/10.1095/ biolreprod.116.140566
Developmental Biology
F
or the first time, it was shown by Wolfwicz, I. et al that Aiptasia larvae can distinguish between compatible and incompatible symbionts during both uptake into gastric cavity and phagocytosis. These findings strengthen the role of Aiptasia larvae as a model system to study endosymbiosis establishment. In the field of biology of reproduction, Lima, A. C. et al. established a transversal method to isolate male germ cells in different mammalian species and across different developmental stages which will have an important impact in the future studies of male reproductive biology.
38
Vale, P. F., & Jardine, M. D. (2016). Infection avoidance behaviour: viral exposure reduces the motivation to forage in female Drosophila melanogaster. Fly, 0. http://doi.org/10.1080/19336934 .2016.1207029 Ruivo, M. T. G., Vera, I. M., Sales-Dias, J., Meireles, P., Gural, N., Bhatia, S. N., … Mancio-Silva, L. (2016). Host AMPK Is a Modulator of Plasmodium Liver Infection. Cell Reports, 16(10), 2539–2545. http://doi.org/10.1016/j.celrep.2016.08.001 Tecuapetla, F., Jin, X., Lima, S. Q., & Costa, R. M. (2016). Complementary Contributions of Striatal Projection Pathways to Action Initiation and Execution. Cell, 166(3), 703–715. http://doi.org/10.1016/j. cell.2016.06.032 Gremel, C. M., Chancey, J. H., Atwood, B. K., Luo, G., Neve, R., Ramakrishnan, C., … Costa, R. M. (2016). Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation. Neuron, 90(6), 1312–1324. http://doi.org/10.1016/j.neuron.2016.04.043 Oliveira-Maia, A. J., Garcia-Guarniz, A.-L., Sinanis, A., Pascual-Leone, A., & Press, D. (2016, June). Comparative Efficacy of Repetitive Transcranial Magnetic Stimu sion Using 2 Different Stimulation Devices: A Retrospective Open-Label Study. The Journal of Clinical Psychiatry. United States. http://doi.org/10.4088/ JCP.15l10275
Parasitology and Infection
A
new potential target to control malaria was found by Man cio-Silva, L. et al. that demonstrate that activation of host AMPK signalling pathway impairs the intracellular replication of malaria parasites during hepatocyte infection. Vale, P. F. et al. found that Drosophila females can avoid infectious environments if they have been previously exposed to Drosophila C Virus, which will be important to understand how the disease spreads in natural populations.
NEUROSCIENCES
E
arly this year Costa, R. M. et al. suggested that targeting the endocannabinoid system may be useful to reduce habitual control over behavior in patients suffering of OCD and addiction that have the inability to shift between habitual and goal-directed actions. In another study, Costa, R. M. et al. with the use of optogenetics manipulation showed that the two basal ganglia pathways (direct and indirect) are required to start a sequence of actions and its performance. The indirect pathway is important to prevent switching between actions whereas the direct pathway informs the animal what action it should continue to perform. It seems that the direct pathway is hyperactive in OCD patients; on the other hand, ADHD patients seem to have a dysfunction of the indirect pathway.
39
Cotovio, G., & Oliveira-Maia, A. J. (2016, September). Hypomania induced by a Garcinia cambogia supplement. The Australian and New Zealand Journal of Psychiatry. http://doi. Barbosa, J. P., Neves, A. R., Silva, A. M., Barbosa, M. A., Reis, M. S., & Santos, S. G. (2016). Nanostructured lipid carriers loaded with resveratrol modulate human dendritic cells. International Journal of Nanomedicine, 11, 3501–3516. http://doi. org/10.2147/IJN.S108694
Nanomedicine and Cell Biology
I
n the field of nanomedicine, Santos, S.G. et al. showed that nanostructured lipid carriers can effectively deliver both fluorescent labels or bioactive molecules, as the natural anti-inflammatory molecule resveratrol, to dendritic cells. The nano-carriers were internalized by dendritic cells without toxicity and were able to modulate an inflammatory response. The biology behind endoplasmic reticulum was on the spotlight with the work of Carvalho, P. et al that discovered a new function of endoplasmic reticulum-associated protein degradation (ERAD) called “protein spatial control” that decides if a protein is going to be degraded or not based on its localization instead of its folding status and Santos, A. J. M. reported how endoplasmic reticulum exports large secretory cargoes.
Ruggiano, A., Mora, G., Buxo, L., & Carvalho, P. (2016). Spatial control of lipid droplet proteins by the ERAD ubiquitin ligase Doa10. The EMBO Journal, 35(15), 1644–1655. http://doi. org/10.15252/embj.201593106
***
Santos, A. J. M., Nogueira, C., Ortega-Bellido, M., & Malhotra, V. (2016). TANGO1 and Mia2/ cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/ VLDLs from the endoplasmic reticulum. The Journal of Cell Biology, 213(3), 343–354. http:// doi.org/10.1083/jcb.201603072
40
The elections for ATG boards are coming soon! Election for ATG board will be held at the ATG general assembly in January 2017. If your are interested to run, please check the by-laws at atg.up.pt
41
ATG News Pedro Resende & Eurico Morais de Sá RECENT GRADUATES António Pinto Almeida, GABBA 15th. Thesis: “Praziquantel-resistance in Schistosoma mansoni: role of efflux pumps, phenotypic characteristics and proteomics analysis”. Supervisors: Ana Júlia Pinto Fonseca Sieuve Afonso - Instituto de Higiene e Medicina Tropical da Universidade Nova de Lisboa. Defense date: 07-07-2016.
Ana Cristina Lima, GABBA 15th. Thesis: “Exploring the regulatory networks of spermatogenesis: from candidate gene approaches to integrative functional genomics”. Supervisors: Alexandra Manuel Ferreira Lopes - ICBAS UP. Defense date: 07-20-2016.
André Lindo, GABBA 14th. Thesis: “Wirelessly controlled micro-and nanostructures for bioapplications” . Supervisors: Bradley Nelson and Salvador Pané i Vidal - Institute of Robotics and Intelligent Systems (IRIS), Swiss Federal Institute of Technology in Zurich (ETHZ); Ana Paula Gomes Moreira Pêgo - I3S/ICBAS UP. Defense date: 09-032016. André is now a P&C Products Controller at Swiss Re in Zürich, Switzerland. Filipa Rijo-Ferreira, GABBA 14th. Thesis: “Circadian rhythms in a Trypanosoma brucei infection: host, parasite or both?”. Supervisors: Luísa Figueiredo (iMM, Lisbon), Joseph Takahashi (UTDallas, Dallas, USA). Defense date: 20-07-2016. Filipa is now starting a postdoc focusing on malaria and circadian rhythms at the Takahashi Lab.
42
MORE ATG NEWS
Diana Saleiro, GABBA 12th, saw her postdoctoral NCI-funded training grant in Oncogenesis and Developmental Biology recently renewed. It will fund her 4th year as a postdoc fellow at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago.
Jose Santos, GABBA 13th José Santos started a post-doctoral position in the group of Petr Broz at the Biozentrum, Basel, Switzerland.
João Curado, GABBA 12th João Curado is now CEO and Bioinformatics researcher at “Flomics”, CRG, Barcelona.
43
For more information on the symposium*: http://www.fchampalimaud.org/ en/newsroom/landscapes-lymphocyte-itineraries-symposium-professor-maria-de-sousa-tribute-view/?p=1
Maria de Sousa. “Landscapes on Lymphocyte Itineraries” symposium* was held in honor of ATG Maria de Sousa at the Champalimaud Foundation, 26 May 2016. This symposium gathered other well-known scientists, who along with the other participants, “celebrated science, curiosity, initiative and knowledge, but, above all, paid tribute to Professor Maria de Sousa for her invaluable contribution to the current panorama of scientific research in Portugal”. More recentlty, on November 24, 2016, Maria de Sousa was knighted as Grand-Cross of The Order of St. James of the Sword by the Portuguese Republic. Congratulations!
Image retrived from http://www.presidencia.pt/?idc=10&idi=118337
Please follow us on Facebook for more news!
Sobrinho Simões. ATG Sobrinho Simões was awarded the Ciência Viva Montepio Grand Prize 2016. Congratulations!
Henrique Veiga Fernandes. ATG Henrique Veiga Fernandes was recently awared the Pfizer Prize 2016. Congratulations!
GPS, Global Portuguese Scientists, was just launched to connect Portuguese scientits over all the world. Have you registered? https://gps.pt *** 44
GABBA News GABBA SYMPOSIUM Breaking boundaries in Science – learning how to get on the shoulders of giants Joana Wilton & Rita Gomes
O
n July 15th 2016, the Salão Nobre at ICBAS was filled with students, investigators and GABBA program directors, all excited about learning with six outstanding scientists.
On July 15th 2016, the Salão Nobre at ICBAS was filled with excitment about six outstanding speakers:
Samuel Sánchez
Tim Sparwasser
Mark Headley
Samuel Sánchez opened the symposium. He is a very upbeat PI at Max Planck Institute for Intelligent Systems and the Institute of Bioengineering in Catalonia (DE/ES) and who talked about his invention: nanorobots for biosensing and drug delivery applications. His multidisciplinary research groups explore the micro and nanoscale physics to understand human physiology. The second speaker was Tim Sparwasser, PI at the Institute of Infection Immunology at Twincore Helmholtz Centre for Infection Research (DE). He presented a historic and charming view of pathogen- and microbe-associated molecular patterns and their impact on targeting immune cells and improving vaccination strategies for major diseases such as tuberculosis and AIDS. Mark Headley, postdoc from the Krummel lab at University of California, San Francisco (USA) was the next speaker. He was extremely enthusiastic to tell us about the recruitment of immune cells by circulating tumor cells, which was only possible to observe through real-time 3D 45
Cláudia Cavadas
João Passos
Renata Pasqualini
in vivo imaging. His research made it possible to distinguish the cellular dynamics arising from normal and pathogenic nascent behaviors in the immune system, such as organ-specific autoimmunity and tolerance to tumor cells. The afternoon talks started with Cláudia Cavadas, from University of Coimbra (PT) who described the recent work of her lab unraveling the activity of neuropeptide Y and caloric restriction as anti-aging players in the hypothalamus. Their work is especially relevant in diseases causing premature aging, such as Hutchinson Gilford Progeria Syndrome. João Passos, a PI from the Institute of Ageing at Newcastle University (UK) and GABBA 6th alumni, delighted the audience by showcasing his groundbreaking work in the characterization of the mitochondria role in promoting cellular senescence, ending with a timely observation on the public perception of research. The closing speaker of the symposium was Renata Pasqualini, co-leader of the Arap-Pasqualini group at the University of New Mexico Comprehensive Cancer Center (USA). She co-chairs a prolific multidisciplinary lab with the broad aim of mapping the human vasculature. During her session, several new targets for cancer theranostics and imaging were brilliantly described, including patented medical devices aiming to increase the patients’ quality of life. Attending these fascinating and diverse talks led us to debate the limits of science, in a debate skillfully chaired by João Relvas, PI from IBMC/i3S (Porto, Portugal). Each speaker, session chair, and an invited ethics researcher brought forth their personal view on the subject, discussing how their research field and other important conditioning factors, such as financing support, technology, politics, among others limit their scientific achievements. The audience was invited to contribute to the debate and the discussion continued even outside the Great Hall in a lively Porto d’Honra served on the foyer. The organizing committee notes that this mission could not have been accomplished without the engagement of our helpful sponsors and enthusiastic audience. The audience in the ICBAS Main Auditorium were enthusiastic and actively participating in each speaker session. After the Symposium, the 19th edition GABBA students will set off for their own paths, hoping to build on the previous knowledge in Biology and, each standing on their chosen shoulder, to Break the Boundaries of Science. *** 46
Our annual meeting is around the corner! See you soon! We are looking forward to GABBA annual meeting! Our annual ATG meeting will be held on December 19, 2016.
47
Read ANd Highlighted My Own Life Oliver Sacks on Learning He Has Terminal Cancer André Sousa & Helder Araujo
A
“ month ago, I felt that I was in good health, even robust health. At 81, I still swim a mile a day. But my luck has run out — a few weeks ago I learned that I have multiple metastases in the liver. Nine years ago it was discovered that I had a rare tumor of the eye, an ocular melanoma. The radiation and lasering to remove the tumor ultimately left me blind in that eye. But though ocular melanomas metastasize in perhaps 50 percent of cases, given the particulars of my own case, the likelihood was much smaller. I am among the unlucky ones. I feel grateful that I have been granted nine years of good health and productivity since the original diagnosis, but now I am face to face with dying. [..] It is up to me now to choose how to live out the months that remain to me. [...] ... one line from Hume’s essay strikes me as especially true: “It is difficult,” he wrote, “to be more detached from life than I am at present.” Over the last few days, I have been able to see my life as from a great altitude, as a sort of landscape, and with a deepening sense of the connection of all its parts. This does not mean I am finished with life. On the contrary, I feel intensely alive, and I want and hope in the time that remains to deepen my friendships, to say farewell to those I love, to write more, to travel if I have the strength, to achieve new levels of understanding and insight. My Own Life Oliver Sacks on Learning He Has Terminal Cancer http://www.nytimes. com/2015/02/19/opinion/oliversacks-on-learning-he-has-terminal-cancer.html?_r=0
This will involve audacity, clarity and plain speaking; trying to straighten my accounts with the world. But there will be time, too, for some fun (and even some silliness, as well). I feel a sudden clear focus and perspective. There is no time for anything inessential. I must focus on myself, my work and my friends. I shall no longer look at “NewsHour” every night. I shall no longer pay any attention to politics or arguments about global warming.
48
This is not indifference but detachment — I still care deeply about the Middle East, about global warming, about growing inequality, but these are no longer my business; they belong to the future. I rejoice when I meet gifted young people — even the one who biopsied and diagnosed my metastases. I feel the future is in good hands. I have been increasingly conscious, for the last 10 years or so, of deaths among my contemporaries. My generation is on the way out, and each death I have felt as an abruption, a tearing away of part of myself. There will be no one like us when we are gone, but then there is no one like anyone else, ever. When people die, they cannot be replaced. They leave holes that cannot be filled, for it is the fate — the genetic and neural fate — of every human being to be a unique individual, to find his own path, to live his own life, to die his own death. I cannot pretend I am without fear. But my predominant feeling is one of gratitude. I have loved and been loved; I have been given much and I have given something in return; I have read and traveled and thought and written. I have had an intercourse with the world, the special intercourse of writers and readers. Above all, I have been a sentient being, a thinking animal, on this beautiful planet, and that in itself has been an enormous privilege and adventure.”
***
49
You reached the end of the third issue of the ATG member newsletter. Will you help us prepare the next issue? You can contribute with material for the existing sections or create new ones. Together, we will make this newsletter grow!
50
ATG - All Time GABBA The Alumni Association of the Graduate Program in Areas of Basic and Applied Biology University of Porto - Portugal