Cardiff University Evans discovered embryonic stem cells in mice, which were used to modify genes in animals for use as models for diseasesCardiff University
in Lindau*
Geneticist Martin Evans was born on January 1, 1941 in a district of the city of Stroud, about 180 km west of London. He recalls what he refers to as his first experiment. In a rural setting where the vision of World War II prisoners who worked in the local fields left its mark, the young Martin Evans watched what others were doing and mixed water with sand and cement, hoping to obtain a solid material. But too much water spilled out and his formula did not work. Half a century later, in 2007 to be exact, Evans received the Nobel Prize in Medicine along with Mario R. Capecchi of the United States and Oliver Smithies of the United Kingdom for his contribution to the development of a cell programming formula which, unlike the old cement that didn’t work, this time he succeeded: He discovered embryonic stem cells in mice. They were genetically manipulated, and animal models were created – knockout rodents – which reproduce the clinical conditions of human diseases. This technique deliberately turns a gene off; by doing so, it causes the same clinical condition or a similar disorder in mice that can strike humans.
Since 2012, Evans has been serving as honorary chancellor of Cardiff University in Wales. He was one of the 37 laureates for the greatest honor science can bestow, and he attended the 64th Nobel Laureate Meeting in Lindau, a small town in southern Germany on the banks of Lake Constance, on the Austrian and Swiss border. At the event, Evans gave lectures and spoke with 600 young scientists from 80 countries, including Brazil. In this interview, at a table at a lakeside restaurant, Evans spoke of the possible impacts of stem cell research on the development of treatments for diseases. “Many stem cell therapies will look more like surgery,” he says. “We need to analyze the risk and the benefit [of these procedures] for people and the environment.”
Will medical research on stem cells generate new treatments for diseases?
I truly believe that stem cells will be part of an important line of therapies. In my opinion, that’s how it should be. But I hope there is strict control over how they will be used. I believe it will be possible to develop highly customized medicine if we are able to achieve this objective, and the risks will be much lower for patients. People fear that there will be a problem with stem cell treatments, and that the patient will ultimately develop tumors, but we are not talking about using a vaccine, which is a large-scale procedure with thousands of people involved. If stem cells generate customized procedures, it will quickly be possible to go back and attempt to solve any patient-specific issues. People will have to ask themselves if it is worth it to put some kind of cell in their bodies. Would they do it for cosmetic purposes? Actually, this has already been done, although I see no reason for doing so. I assume that in cases of esthetics, some people feel that the benefits outweigh the risks. In stem cell treatments, ideally the benefits would be tremendous and the risks as minute as possible.
When will new stem cell treatments become available?
Some are already in use at the experimental level. There are studies on treatments using cells in the retina. Some people think it is terrible to perform these tests on the eyes, but it’s the ideal spot because eyes are isolated organs. The worst that can happen is that the patient loses vision in the eye, which would have occurred in any event, even without the treatment. The adoption of cell therapies will be a slow process. My standard answer to this question, though it may be incorrect, is that I don’t believe that I or anyone else of my generation will benefit from these new treatments. And I don’t think your generation will benefit either. I suspect that people who are born now have great opportunities for using these procedures 50 years from now. That’s my opinion. But there will be many different examples of treatments. Stem cells will be an important type of intervention along with pharmaceutical approaches and probably gene therapy. I hope that these treatments are not highly problematic, as was the case with gene therapy research, in which studies that were performed in this field were halted for a decade.
ROLF SCHULTES/LINDAU NOBEL LAUREATE MEETINGSThe English geneticist at a meeting in Lindau with young researchers: stimulus for new generationsROLF SCHULTES/LINDAU NOBEL LAUREATE MEETINGS
Besides the technical issues that have yet to be overcome, research using stem cells obtained from human embryos faces ethical questions. What is your view of this situation?
I have always worked with embryonic cells from mice. There are restrictions on animal research, but it’s not like humans. Everything I say comes from my ideas about human stem cells. I have served on committees that deal with this. We are in the midst of a process in which we and the public have to understand where we are. Some slight progress is being made in research laboratories, but the most important decisions will have to be made once the therapies begin to move out of the laboratories and can be used in patients. We will have to see whether things that have been done on a small experimental scale can be considered ethical if they are implemented on a large scale. We will have to analyze the risk and the benefit for people and the environment. We must take into account who will reap the benefits and who will shoulder the risks. And that is how we will be able to make rational and informed decisions.
Do we really have reason to be hopeful that induced pluripotent stem cells (iPS) can help develop new theories?
Things are changing rapidly. We used to think that treatments would come from embryonic cells, but there are cells that are virtually able to behave like embryonic cells and generate different tissues when a special chemical treatment is used. These cells, known as iPS, can be taken from human skin and there are many different methods for producing them. In this case, we are talking about cells that can come from a source that is much less controversial than embryonic cells, in other words, other adult cells. I believe that the best treatments will come from cells taken from the patient who is actually being treated. Many standards on the use of stem cells that we are using are an extension of the regulation of the pharmaceutical sector, but these two areas are not exactly the same. In the case of drugs, it is necessary to perform many clinical trials, because this is a type of treatment that, if approved, will be prescribed for millions of people. In the case of stem cell treatments, many of the therapies will be more like surgery. I would go back to the example of experiments in which stem cells are used to attempt to treat certain types of blindness. Even though we are using stem cells, we are talking about a type of operation that takes place in the eyes. The procedure involves individual risks and benefits. Patients may believe it is worthwhile to undergo the procedure if they know they risk losing their vision if they opt not to have this surgery. The decision to go ahead with the operation will affect one person only and no one else.
Are you convinced that iPS cells are really very similar to embryonic cells?
We need to look at two aspects of this: First, I would say that they are very similar; second, not all embryonic stem cells are good. The same is true for iPS cells. At this time there are at least 12 different procedures to obtain iPS cells, all of which are based on the initial observations of Professor Shinya Yamanaka [of the University of Kyoto, who won the Nobel Prize in Medicine in 2012 for successfully reprogramming adult cells to behave as embryonic cells and thus, to revert to being pluripotent]. According to Yamanaka, to turn fibroblasts [skin cells] into iPS cells, it was necessary to introduce four different transcription factors [actually, it was necessary to insert four genes that produced proteins called transcription factors that regulate how other genes in cells work]. Today there are people who have done this successfully with three factors and they have obtained this result that yields proteins or RNA in adult cells. It takes time to reprogram cells. Obviously, many processes take place inside cells and we need to understand them. But this reprogramming of an adult cell into an iPS cell that is similar to an embryonic cell is the most dramatic turnaround in terms of cell development and differentiation; it is a 180-degree turnaround. As Professor Yamanaka himself would tell you, he succeeded in doing this only because he already knew how to grow embryonic cells, what the requirements were and how they were. For me, it is clear that we are entering a new era in which we will have the technical knowledge and capability to convert one type of cell into another. This way, researchers are making nerve and muscle cells, and cell biology is truly making headway.
In the last few years, some scientific articles that described alleged major advances in stem cell research were seen as incorrect or fraudulent and publication was canceled. How do you see this?
In my field, there have been five or six of these dramatic episodes and I wonder if they are special cases. We know there are ethical questions and interests involved in these instances. There was that well-known case of the South Korean [Hwang Woo-suk, who published two fraudulent articles in Science in 2004 and 2005]. Regarding this most recent case [an article from January written by a Japanese team from the Riken Center for Developmental Biology, published in Nature], the results seemed highly unlikely. I was surprised that the journal published the work without thinking seriously about it.
Should scientific journals be more cautious about accepting works for publication?
I have to answer yes and no. If journals are extremely selective about what they believe is correct, then they will actually not be doing their job. Publishers should not put themselves in that position. But their editors should, as they need to discuss whether or not the work that is submitted is likely to be accurate. In this work at the Riken Center, clearly there were illustrations that did not show what they said they were showing. We are not in a position to say whether this was deliberate fraud or whether it was an excessively optimistic interpretation of the images. To be sure, the work was inaccurate. But we don’t know how or why. I tend to believe it was an overly optimistic interpretation. But let’s put it this way: Questioning the process of publishing work is certainly justified.
What was the impact of creating knockout mice that turned into animal models for studying diseases?
Today a knockout mouse must be developed for a host of diseases. Even researchers are complaining about it, but it has to be done. I showed a slide in my lecture in which, according to one forecast, sales in the knockout mouse market will amount to $1.8 billion in 2018. What does this mean? I can’t say. We estimate that more or less half of the genes have already been knocked out. Today, some people are even doing the opposite of what we had to do in the past. It used to be that we found a phenotype in an experiment using animals or a patient and we had to look for the mutation that caused it. Today, we can force mutations to present a phenotype. This way, we can recognize them.
What type of research are you conducting now?
I am not doing any research. I am retired. I talk a bit to younger colleagues, but I am not doing any lab work. I write a few articles and I am also affiliated with a company that makes stem cell treatments. But I am not doing much.
What changed in your life – professionally and on a personal level – after you won the Nobel Prize?
When I received the prize, I was retiring from Cardiff University. But they wanted to keep me and give me an honorary position. In the final years, I was chancellor of the university. You are inundated with invitations when you win a Nobel Prize. It’s very difficult to deal with. I have been very happy and the university has always supported me. They gave me a personal assistant and that’s very helpful.
This is your second trip to Lindau. Why did you accept the invitation again?
After the Nobel Prize, they told me that I would be invited to come. The atmosphere in Lindau is wonderful, it’s a beautiful spot, and the event is very well organized. Meeting other Nobel laureates is terrific, and I love the multidisciplinary aspect of the conversations. And, clearly, there are the meetings with young students. At every point in my life I have interacted with younger people and encouraged them. I enjoy this very much.
Are the younger generations interested in science?
Yes, I think many people are interested in research. But there are problems with the way science is taught in schools. Science is an intellectual discipline. It’s an activity similar to that of poets and artists. I think people should be interested in more than just one thing. I would certainly never think of science as just the basis for possible applications of technology. This aspect is good. All of us benefit from technical advances in medicine and other fields. A career in medicine – and I am saying this only because I have friends in that field – may be very lucrative. But the best clinics I know are the clinics that think about the profession.
* Marcos Pivetta traveled to Germany at the invitation of the German Academic Exchange Service (DAAD)
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