Professor of Immunology and Genomic Medicine
Kyoto University Graduate School of Medicine
AsianScientist (Jun. 13, 2016) – Tasuku Honjo, an immunology and genomic medicine professor at Kyoto University in Japan, has been a lab researcher for almost half a century—and is not showing any signs of stopping.
Honjo’s contributions over a long, fulfilling career have shaped the field of immunotherapy, opening up a new therapeutic era for cancer. He is best known for two major discoveries: the role of programmed cell death protein 1 (PD-1) in the immune response, and the activation-induced cytidine deaminase (AID) enzyme that is essential for class switch recombination.
Among the numerous awards and honors that Honjo has received are the Order of Culture, the Robert Koch Prize, and the Imperial Prize of the Japan Academy. He is a foreign associate of the US National Academy of Sciences and a member of the Japan Academy. In 2014, his pioneering role in discovering PD-1 earned him the inaugural Tang Prize in Biopharmaceutical Science.
Below, Honjo shares with Asian Scientist Magazine some insights into his discoveries, current pursuits in the lab, and personal research philosophy.
What first drew you to the field of immunology?
I originally studied as a biochemist. But during graduate school, I also got interested in immunology. After I moved to the US as a postdoctoral researcher in the 70s, I met my mentor, Dr. Donald Brown, at the Carnegie Institution for Science in Baltimore. He told me that the major question of immunology at the time was, how do we create such an enormous diversity of antibodies? That question is now ready to be tackled using a molecular strategy.
- What was your role in the discovery of PD-1?
We discovered PD-1 in 1992 when we were actually looking for something else. So in a way, we accidentally ‘bumped into’ this molecule. We thought that PD-1 protein, which is expressed on activated T cells, was quite interesting, so we went on to study the function of this protein.
We deleted the corresponding genes in mice to make knock-out animal models and tried to see what happened. As it turns out, those mice began to exhibit various immune diseases, which suggested that PD-1 was suppressing their immune response.
We theorized that by suppressing PD-1, you could boost immune response and hopefully treat cancers that way. That was the starting point: we showed in a study published in 2002 that PD-1 blockade can indeed cure cancer in animal models.
From there, it took another 12 years for us to reach the clinic. In 2014, our anti-PD-1 antibody therapy was approved by the FDA as a drug to treat melanoma. From discovery to clinical application, it took us 22 years; a long time!
- PD-1 blockade has been hailed as a major advance in cancer immunotherapy. What do you feel are the most promising recent developments in this field?
I have not heard about any other developments of note. PD-1 immunotherapy is now at the stage where researchers are attempting to expand on the applications of the target. Researchers are finding ways to extend the treatment to other types of tumors, or to develop combination immunotherapy: PD-1 coupled with a drug to boost efficacy of treatment. In this area, many companies are still conducting tests, but so far we have not heard of any promising results.
- What is immunoglobulin class switching and why is it important for a healthy immune system?
When you give a vaccine to a patient, their immune system recognizes the antigen and begins to produce antibodies. The first antibody the body produces as part of immune response is usually immunoglobin M (IgM). It can bind, but it’s not really useful for killing the bacteria or virus.
In most cases, you need immunoblobin G (IgG), a higher afinity antibody—especially for those infections through the mucosa (lining) in the nose, throat, lung or intestine. The best antibody to protect from infections, however, is immunoglobin A (IgA). So you need a change of the class of immunoglobins from IgM to IgG or IgA; this is very important for immune protection.
- How did you show that AID was important for class switching?
We discovered this enzyme, which is required for class switching, in 2000. When we made AID knock-out models, the mice could not carry out class switching. Simultaneously we found AID is involved in somatic hypermutation. Somatic hypermutation is essential for making strong-binding antibodies.
We collaborated with a research group in France that was looking for the gene responsible for the hyper IgM syndrome type 2 genetic disease in humans. Patients with this disease possess high levels of IgM which cannot switch to IgG, and therefore, they have severe immune deficiencies.
Once we discovered AID, we decided to test whether those patients have a defect in the AID gene. The French researchers discovered the mutation in all of the Hyper IgM patients, confirming our findings.
- What are your current research pursuits?
Right now, we have a project focusing on PD-1 cancer immunotherapy treatment. There are two aspects: firstly, although PD-1 therapy is very effective, it’s not 100 percent effective. In case of melanoma, 30 percent of patients do not respond to this treatment; the percentage varies depending on the type of tumor. So, we are trying to develop a novel combination therapy to overcome this 30 percent of non-responders. Secondly, we are hoping to be able to identify responders and non-responders before treatment, by [looking at] their biomarkers.
- Throughout your years of research, what were some of the challenges that you faced and how did you overcome them?
When we were working on understanding the function of PD-1 after we knocked out the PD-1 gene in mice, we waited for something to happen. But for a year, nothing did; the mice were perfectly OK. We consulted an immunology expert, who advised us to use purebred mice. Mice with a heterogenous lineage are very ‘strong,’ so it won’t be easy to see the effects on their immune system.
We had to carry out ten generations of mating—that alone took more than a year. It was a painful time. You have to wait and wait, and still, you just continue.
- What is your personal research philosophy?
If you look at my lab homepage, there I list three words: curiosity, courage and challenge. Most important is curiosity; you have to have curiosity. You also need courage to challenge big questions. To work in science, that’s most important.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Tasuku Honjo/Kyoto University.
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