Alberto Orfao, hematologist: "We are working to detect the risk of leukemia 20 years before it appears."

Alberto Orfao (Lisbon, 65) is a researcher who doesn't force headlines or make too many concessions to simplifying complex problems. He explains his current projects with precision and recalls how medicine has changed in his three decades of experience, partly thanks to work like his. The European Hematology Association has just recognized him with the Research Excellence Award for his more than 800 scientific articles in hematological research and, in particular, for his contribution to the early detection of leukemia, a field in which he has also registered 70 patents that reflect the innovative nature of his group's work.

In a hotel in Madrid, he acknowledges that, when he began his career, all these advances "were unthinkable." Now, he's working to anticipate the diagnosis of leukemia by more than fifteen years, and perhaps in the future, of other tumors, in order to treat them before they cause any damage. He seeks the key in monoclonal B-cell lymphocytosis (MBL), an asymptomatic condition in which elevated levels of clones of a type of lymphocyte appear in the blood. All people who eventually develop leukemia begin with this MBL, some before they turn 50, but only a few of those with these clones actually develop the disease. The goal now is to identify those truly at risk.

Question: Many people have MBL, but very few go on to develop leukemia. How can these markers be used for diagnosis?

Answer: We wanted to develop technology to detect diseases in their very early stages, but when we get to those early stages, we see that almost everyone has something. MBL begins to appear after age 40. The prevalence between 40 and 50 years of age is 5% of adults. Then it increases, and by age 90, the prevalence is over 50%.

And we're not just seeing B-cell MBLs, but also other cell types. There's a similar situation for T lymphocytes, called T-CUS, which we're seeing in 99% of older people. So you start to think: yes, it's true that this cell can be a precursor to leukemia, but it could also be a cell that, with age, is necessary for the immune system to function properly in later life.

Because if everyone who reaches 100 has these types of clones, it clearly doesn't mean that everyone will develop leukemia, but rather that those who live a long time and have a more competent immune system are the ones who have these types of cells.

We've begun to look into the meaning of these cells and have been able to demonstrate that at least some of these clones are directed against viruses that almost all of us have since childhood, and that remain in the body throughout life. These cells seem to be able to control these viruses. It's as if the immune system were saying: "Okay, I have latent viruses inside me. Instead of responding every time I see them, I'll create an expert, specialized cell, so I don't distract the immune system with this thing I already know."

Q. So it would be like a coping mechanism?

A. Exactly. And this serves to say that all leukemias of this type of B cells come from this previous stage, from these MBL clones. But since so many healthy people have them and the vast majority don't develop leukemia, we think they are cells that must have a physiological, that is, normal, role. The body acts intelligently and isn't stupid, so to speak.

What appears to be happening is that these cells, in a normal individual, begin to appear or expand, especially after the age of 40. And now, with technology, we can see them. But for them to transform into leukemia, other factors must intervene.

Q. Do you have any clue as to what those factors might be?

A. We're looking for it, although our results are sometimes contradictory. For example, after the pandemic, we analyzed a cohort we had previously studied, and we're seeing that, 15 years later, those who had these cells are dying more, especially from infections and cancer. On the contrary, during the pandemic, many older people died. And the curious thing is that those who didn't have these clones were the ones who died the most from infections, precisely during that period. In other words, their immune systems didn't function as well in the unusual situation of the pandemic. It would seem that having these cells could protect you in certain unusual contexts, but not in other situations where it seems clear that those with these clones have an immune system that doesn't function as well. Although it's not necessarily due to progression to leukemia. We've seen some cases that did progress to leukemia, in which we detected MBL clones at age 60 and who ended up developing leukemia at age 84, for example. But in the vast majority, this doesn't happen.

We are now continuing to investigate what factors cause some to progress to leukemia. We have found some cell characteristics that could reduce this risk group to 10%. Our current hypothesis is that some cells could be under continuous stimulation mediated by common environmental signals—not serious infections, but common signals—and this causes them to grow more.

It also appears that in individuals in whom these cells grow more, their defense system at the barrier level (intestinal, respiratory) may be weakened. That is, instead of defending you before something enters, it does so after it has crossed the first defense barrier. Your immune system is then forced to respond internally to stimuli that normally wouldn't enter the body, and this could facilitate the stimulation of these clones. This growth is clearly associated with the appearance of genetic alterations typical of leukemia. In some cases, this growth is triggered, perhaps because these alterations accumulate in unique combinations.

That's where we are now, trying to unravel that puzzle. What we do know for sure is that the presence of small clones of cells identical to those we see in the leukemia stage is very common. So common that we can almost say it's normal, since if you live a long time, you're going to have these clones. And if they were normal, they must have a function that we still don't know.

We're also sure of something else: no one develops this type of leukemia without having had these cells first. So they're the necessary source. If you don't have them, you won't develop this type of leukemia.

These are the cells that transform into tumors. That jump exists! And we see that these cells grow over the years, but not at a rate that necessarily results in leukemia, even if you live to 100. There must be factors that trigger faster growth.

Q. In addition to the potential diagnostic value, I understand that if we gain a better understanding of this puzzle, there's also the possibility of having some control over this transformation? Some blocking mechanism that could prevent the disease.

A. There could even be treatments with very little toxicity, which could be administered to healthy subjects at risk. But to do that, the risk group must first be clearly identified. In the early stages, even of leukemia, people are fine. They get a blood test and the disease is detected. And because these are such early stages, no treatment is administered: a "wait and see" attitude is adopted. Some progress quickly, others don't.

In these early stages of leukemia, within the ECRIN-M3 (Early Cancer Research Initiative Network) consortium, funded by the Scientific Foundation of the Spanish Association Against Cancer (and Loterías), together with its counterparts in Italy and the United Kingdom, we have developed predictive models. I diagnose you today, and you don't need treatment, but with these models I can establish a probability of, for example, 90%, that in five or 10 years, you won't need it either.

In other cases, a preventive strategy could be established, when the probability of progression is high: 70% after one year, for example. In the 1980s, diagnosis was given when someone felt ill, went to the doctor, and the leukemia was found to be already developed and usually advanced. Now, with routine blood tests, it's detected earlier. But if there are no symptoms, it's not treated immediately. Increasingly, we want to be proactive. If we know who's going to get sick, we might be able to intervene earlier. We could even consider it in healthy individuals with high MBL counts. And there will certainly be clinical trials in this regard.

We're working on even earlier stages: 20 years before the onset of leukemia. That's especially important for young people. It doesn't make much sense for someone 80 years old. But for adults in their 20s or 30s, it might. That's why we began studies in adults as young as 18 a few years ago.

Q. Could this technology also be applied to solid tumors?

A. Of course. Today we think it's the toxicant that induces the genetic alteration. But it could also be that the cell, as an intelligent entity, responds to the toxicant by creating protective mechanisms. Resistant cells, difficult to eliminate, that grow, only sometimes in an uncontrolled manner. These latter are tumor cells.

This completely changes the way we understand treatment. If we want to slow progression, we must consider physiological mechanisms, not only DNA repair but also DNA modification.

Q. What do you think about the future of diagnostics, of precision medicine?

A. Precision medicine has contributed to numerous notable advances. However, today's precision medicine should change its name. Today, precision medicine is identified with massive analyses of many parameters, in the hope of finding one or more that are key. These massive analyses are the exact opposite of what precision means. We need to move toward what I would call ultra-precision medicine: identifying the cells responsible for a disease, even if they are in a very specific tissue and in very small numbers.

With current precision medicine tools, none of this is visible. It's below the threshold of detection. Precision medicine is like looking at a world map and only seeing what's above the water, often with very low resolution. But the disease can be at the bottom of the ocean. We need much more sensitive, ultra-precise tools.

I'm sure this will lead to reclassifying or identifying disease mechanisms, perhaps for many diseases. This is the recent case of anaphylaxis: we now know that many patients have a mutation that activates a specific cell, and this seems to explain why that cell reacts differently, leading to much more severe symptoms than, for example, we see in a typical allergic or atopic response to the same medication or stimulus.

Q. There's one last question, not directly related to your research, but rather to the academic prestige of the institution where you work. As you know, our newspaper has reported on the academic fraud committed by the rector of the University of Salamanca. For someone as prestigious as yourself, how do you feel about your rector having 75 articles retracted from scientific journals?

A. I believe that researchers and university professors should have ethics that go beyond norms and laws, which are also good to have, by the way. Even if one doesn't seek recognition, like the award we began this conversation with, the most gratifying aspect of research is seeing that what you described as a group is used and useful. That others reproduce it. Society should be able to evaluate this beyond specific individuals. The important thing in these specific cases is, without a doubt, being able to know the truth, and to transparently understand what happened and why. I am proud of each member of the group, not only for the results of the research, but also for its rigor and for never having had a retraction after more than 800 published papers.

Q. Precisely for that reason. You, who have never had a withdrawal, do you feel comfortable having someone in that situation as the highest representative of your institution?

A. It's not comfortable, of course, even if it's a rector elected by an absolute majority and I hope he will energize the institution. Personally, I think the important thing in these types of situations is to know exactly what happened, why, and how. And for all of this to come to light in the most transparent way possible, so that we can truly understand what happened and, above all, contribute to preventing such situations from happening again. Without this clear explanation, it's logical that doubts will persist beyond what would be desirable. I think it's something that should be applied even more widely to other areas of public life, always and particularly in these times when we witness, perplexed, so many situations of dubious ethical behavior.