Advisory Board

Professor Manuel Serrano

Manuel Serrano, Ph.D., is ICREA Research Professor, Coordinator of the Ageing and Metabolism Programme, and Group Leader of the Cellular Plasticity and Disease Group, at the Institute for Research in Biomedicine (IRB) of Barcelona, Spain. ICREA is the Catalan Institution for Research and Advanced Studies, a foundation supported by the Catalan Government.

Manuel is internationally recognized in the field of tumor suppression. In addition to the discovery of p16, one of his main discoveries has been the identification of cellular senescence as the main anti-oncogenic response. Recently, his laboratory has also shown that cellular senescence participates in several tissue remodeling processes during embryo development. His team was a pioneer in the generation of genetically-modified mice resistant to cancer and found a link between tumor suppressor genes and aging.

In recent years, his research interests have extended to metabolism and cellular reprogramming in relation to aging. His laboratory was first in demonstrating that cellular reprogramming into pluripotency is possible within an organism, and this discovery was considered Advance of the Year 2013 by Nature Medicine. More recently, Manuel has reported in Science that in vivo reprogramming is enhanced by the coexistence of tissue injury thanks to the production of interleukin IL-6.

The focus of his laboratory is now to apply their knowledge on senescence and reprogramming to degenerative diseases such as lung, kidney, and heart fibrosis.

Manuel is the chair of The Aging and Metabolism unit. The programme focuses on deciphering the mechanisms underlying the aging process and associated disruptions in metabolic pathways. Research efforts into these fields seek to develop precision therapies for aging-related diseases, putting an emphasis on multi-morbidities, with the purpose to ensure healthy aging.

He is also the leader of the Cellular Plasticity and Disease group where they are working on unifying the research on tumor suppressor genes that protect from many types of damage regardless of the particular detrimental consequences of the damage. In other words, tumor suppressors protect from damage even if that damage is not going to produce cancer, but a degenerative disease. According to this view, cancer protection is just one of the outcomes of tumor suppressors, with other outcomes being protection from chronic diseases, from nutritional overload, from tissue injuries, or from aging.

Manuel earned his Ph.D. in 1991 for his research at Centro de Biologia Molecular (CBM) under the supervision of M. Salas and J.M. Hermoso. From 1992 to 1996 he worked as Postdoctoral Fellow in the laboratory of D. Beach at the Cold Spring Harbor Laboratory, New York, USA. In 1997, he returned to Spain to start his own research group at the Centro Nacional de Biotecnología. He moved to the CNIO in 2003 to lead the Tumour Suppression Group. In May 2017 he relocated to IRB Barcelona to establish the Cellular Plasticity and Disease Group within the Molecular Medicine Research Programme.

In January 2018, Manuel received the Severo Ochoa Prize for Biomedical Research award.

He has accomplished important scientific contributions to the understanding of Ageing from different perspectives: Cancer & Ageing, Metabolism & Ageing, and Regeneration & Ageing. Among his discoveries, the following ones have had special impact:

CANCER & AGEING

1
The discovery, cloning, and characterization of the tumor suppressor p16, which defined a new class of cell cycle regulators and was soon acknowledged as one of the key tumor suppressor genes. Together with p53, PTEN and Rb, the tumor suppressor p16 constitutes one of the four most important cancer protecting genes known to date. In addition, the discovery of p16 paved the way to the discovery of p19Arf, another paramount tumor suppressor.  The tumor suppressor p16 is also involved in the establishment of cellular senescence and it is today the most widely used gene marker of ageing.
2
Establishment for the first time of the concept of "oncogene-induced senescence" as a tumor suppression mechanism, thus opening a new frontier in Molecular Oncology. The former concept speedily became an intense research topic in many laboratories; it is a widely-accepted concept upon which a great deal of expectations for future advances have been deposited.
3
Description for the first time of the identification of senescent tumor cells in vivo. His original discovery of oncogene-induced senescence triggered a cascade of in vitro studies in numerous laboratories. Nevertheless, the question of whether senescence could take place in vivo remained a hotly debated issue.
4
Identification of the function of p19Arf as an oncogenic sensor. This is a seminal work, which characterised p19Arf as the main sensor of the oncogenic signalling for the activation of p53. This initial observation has been the basis of subsequent research that has solidly established p19Arf as the main pathway for p53 activation.
5
Identification of a DNA regulatory element that controls the expression of the tumor suppressor p16/p19Arf locus, which under normal conditions is silent and activates upon the presence of oncogenes. This identification constituted the first step towards the understanding of which ones are the switches activating these important tumor suppressor genes.
6
Pioneering the generation of cancer-resistant mice with the so-called “super-mice”. These works have positively demonstrated the possibility of increasing cancer resistance in the absence of deleterious secondary effects. He also demonstrated that tumor suppressor genes also protect against ageing, thanks to the capacity of these genes to eliminate cellular damage in general.

METABOLISM & AGEING

7
Study of the role of SIRT1 in longevity, cancer, and metabolic protection from high-fat diets.
8
Identification that inhibition of PI3K extends longevity in mice and protects from obesity in mice and monkeys.

REGENERATION & AGEING

9
Identification of the tumor suppressor locus Ink4/Arf as one of the main barriers for nuclear reprogramming of adult cells to induced pluripotent stem cells (iPS), which has also helped in the understanding the cellular mechanisms of defence. Artificial iPS generation by addition of a defined set of transcription factors is an inefficient process and the motives of the resistance to iPS conversion were unknown. Manuel reasoned that since the tumor suppressor genes prevent normal cells from converting into cancer ones, they could also be preventing this other type of cellular “conversion”. Subsequently, he reported similar findings regarding the tumor suppressor p27.
10
Demonstration for the first time ever that reprogramming into pluripotency is feasible "inside" a living organism, bypassing thus the necessity to in vitro manipulate cells. This research was considered by the journal Nature Medicine the "Achievement of the Year 2013" in the stem cell field.
11
Demonstration for the first time ever that during embryo development cellular senescence is a process that promotes tissue remodeling.
12
Discovery that tissue damage promotes pluripotency through the secretion of cytokine IL6 by the damaged/senescent cells.

Manuel’s group is currently focused on the following research:

1
Tissue regeneration in reprogrammable mice.

They are actively studying tissue regeneration in their reprogrammable mice (where they can induce the four Yamanaka factors in vivo) and how this is affected by tissue injury, senescence, and inflammation.

2
Therapeutic effects of elimination of pathological senescent cells.

They have a very original project on the use of silica nanoparticles to deliver drugs selectively into senescent cells. They are focused on their therapeutic potential in pulmonary fibrosis.

3
Manipulating and understanding pluripotency.

With several projects aimed to manipulate and stabilize pluripotency with chemical compounds, both in mouse and in human cells. For example, they can hyperactivate the Mediator complex with a chemical compound and in this manner they can stabilize the naïve state of pluripotency in mouse and human cells. They are attempting to deliver reprogramming chemicals in vivo to enhance tissue regeneration.

4
Targeting pluripotency in cancer.

With a strong line of research on cancer and in this regard they have identified new chemical compounds that selectively target cancer stem cells.

5
Understanding aging.

With several projects aimed to understand the connection between metabolic pathways, tumor suppressors, and aging.

Watch his “Killing zombie cells” video. Read Manuel’s lecture summary at the Karolinska Research Institute. Read his article about Role of the INK4a Locus in Tumor Suppression and Cell Mortality. View his publication list and visit his homepage.