Dan Salah Tawfik (1955–2021)
Liam M. Longo ,Dragana Despotović , Lianet Noda-García
Nature Ecology & Evolution (2021) Cite this article
We are deeply saddened by the premature and unexpected passing of our dear friend and mentor Dan Salah Tawfik (דן סלח תופיק) in a climbing accident on 4 May 2021. Danny was born in Jerusalem in 1955 to an Iraqi-Jewish family, and he cherished both sides of his heritage: he was a Jew and an Arab. Throughout his life, Danny took great pleasure in subverting any simple classification: he was a scientist, a former construction worker, and a retired major in the Israel Defence Forces.
Danny climbing the cliffs at Ein Farah in 2020. Credit: David Salem, Zoog Productions
Danny’s contributions to science were immense, and his insights into enzyme catalysis have shaped an array of fields, including marine biology, metabolic engineering, astrobiology and the origin of life. He is, perhaps, best known for developing in vitro compartmentalization — which links genotype to phenotype in artificial cells — and revealing the critical role of promiscuity in enzyme evolution. For these technical and theoretical advancements, Danny was awarded the prestigious EMET Prize for Biological Science by the Israeli government in 2020.
The major through-line of Danny’s work, enzyme evolution, requires an understanding of forces that operate across vastly different scales of length and time: from the effect of a mutation on protein function (for example, binding and catalysis) to the overall fitness of an organism or a population in the environment. Although Danny was trained as a chemist, he was never constrained by divisions between disciplines. Instead, he deftly navigated his research across and between the different levels of life’s organization, from small molecules and proteins to cells and microbial communities. Restless by nature, Danny was never content to stay put; he was always transforming himself and his lab. In recent years, Danny focused his efforts on understanding early protein evolution, ever eager to uncover biological secrets that are billions of years old. His work helped explain how complex protein structure and function could have emerged from ‘so simple a beginning’ by demonstrating the surprising functional repertoire of short, oligomerizing peptides.
Danny’s success as a scientist can be understood, in part, through his love of rock climbing: namely, his embrace of risk and his persistent desire to challenge himself both physically and mentally. Although the inherent danger of rock climbing can be mitigated with training and practice, it can never be abolished. It was with this attitude that Danny pursued his curiosity and conceived of scientific projects. First, with extensive reading and discussions with peers; then, by setting ambitious goals where risk — in this case, of project failure — was an intentional part of the design. Danny understood that to push the boundaries of human knowledge, as with climbing, you must continually challenge yourself to overcome your limitations. The elevated perspective at the summit — be it views of the desert or a deepened understanding of biological phenomena — was the reward. By embracing risk, Danny was able to consistently ask provocative questions and do important, relevant research, spanning some 30 years and 160 original research articles.
Danny’s legacy also lives on through his unique style of mentorship. In the lab, Danny embraced disagreements and discussions. He suppressed and minimized social or professional hierarchies, instead encouraging everyone to engage in science together as equals. Despite significant responsibility, Danny foremost enjoyed analysing and discussing data and ideas with students in his lab. Irrespective of your lab seniority, Danny had time to meet with you. When results were bad, he brought optimism; when results were good, he brought a critical eye. Indeed, Danny’s optimism was a powerful motivator, especially when the path forward was not clear. He understood the value of rest, of long lunches and of play.
During his years as a principal investigator at the Medical Research Council Centre for Protein Engineering, Cambridge, UK, and the Weizmann Institute of Science, Israel, Danny mentored over 50 aspiring scientists — many of whom have gone on to establish independent research groups. Just as he valued diversity in his research topics, so did he value human diversity, both scientifically and culturally. Danny championed the inclusion of women and under-represented minorities in science. On weekends, he would lecture at underserved schools throughout Israel, hoping to inspire disadvantaged students.
Dan Tawfik was not just a scientific visionary; he was generous and humane. A confident, unpretentious man with a strong passion for science and mentorship. A man who openly embraced risk and playfulness, and ultimately transformed the field of enzymology. He is dearly missed.
https://www.nature.com/articles/s41559-021-01539-4
Obituary: Dan S Tawfik (1955–2021)
Amir Aharoni,Sarel J. Fleishman,
https://doi.org/10.1111/febs.16019
Abstract
Dan (Danny) Tawfik, a leader in biochemistry and protein evolution, sadly died due to a fatal climbing accident on May 4th, 2021. Apart from science, rock climbing was Danny's passion and a source of pride as only a handful of researchers are active climbers. Danny made unique and long-lasting contributions to our understanding of molecular evolution. He was also incredibly generous with his time and insights, and many researchers around the world are indebted to him, not least the two authors of this obituary.
Danny on a mountain climbing trip in Ayn Fa'rah. Picture credit to David Salem, Zoog Production.
Dan (Danny) Tawfik, a leader in biochemistry and protein evolution, died due to a fatal climbing accident on May 4th, 2021. Apart from science, rock climbing was Danny's passion and a source of pride as only a handful of researchers are active climbers. Danny made unique and long-lasting contributions to our understanding of molecular evolution. He was also incredibly generous with his time and insights, and many researchers around the world are indebted to him, not least the two authors of this obituary.
Modern enzyme engineering cannot be understood without the previously provocative but now well-established concepts that Danny pioneered. Early in his academic career, Danny developed in vitro compartmentalization (IVC) technology [[1]]. IVC segregates millions of mutated enzymes into tiny water-in-oil droplets where their activity is probed individually to isolate the most active mutants [[2]]. IVC became a leading enabling technology in clinical genetics and next-generation sequencing. Although Danny was very proud of these applications, his goals were always to gain a fundamental understanding of how proteins function and how they have evolved to their myriad present forms.
Danny applied IVC (and other laboratory evolution techniques) to a variety of enzymes [[3, 4]] and binding proteins [[5]] to simulate the evolutionary processes that alter their activity. Through these studies, he reached a fundamental insight that promiscuous enzyme activities — i.e., side reactions that are distinct from the enzyme's main activity — are a significant source of evolutionary innovation [[6, 7]]. He surmised that an enzyme that exhibits low promiscuous activities could be iteratively mutated until these become the mutated enzyme's primary activities. For instance, Danny studied how enzymes that break down naturally occurring bacterial quorum-sensing molecules might have evolved to break down new-to-nature synthetic pesticides. He thereby found what may be an evolutionary “missing link” that connects the two activities [[8]]. He then harnessed laboratory evolution to engineer the same enzymes to efficiently break down synthetic and highly venomous nerve agents [[9]]. The concept of using weak promiscuous activities as a stepping stone for evolving novel enzymes that exhibit a variety of desirable activities has made a profound impact on protein engineering and has been used extensively by many researchers [[10]].
One of Danny's most important discoveries revealed a fundamental constraint on the evolution of new protein activities. Proteins are complex molecules—in fact, the most complex molecules in nature. They are therefore extremely sensitive to mutation, and most mutations destabilize them. By carefully tracing the evolutionary trajectories of enzymes in his lab, Danny noticed that mutations could enhance promiscuous activities, but frustratingly, only up to a point. At that point, the enzyme has accumulated too many destabilizing mutations and can no longer function [[11, 12]]. The finding of this “stability-threshold” effect has become a cornerstone of modern protein engineering and design [[13-15]]. Danny also proposed innovative and practical solutions to this problem. He first demonstrated how chaperones might assist the folding of marginally stable proteins and enable more efficacious evolutionary processes [[16]]. Later, in collaboration with both of us, we used atomistic protein-design calculations to dramatically stabilize proteins [[17]], enabling the laboratory evolution of even more efficient enzymes for breaking down nerve agents [[9]].
Over the past decade, Danny's focus shifted from studying the small but powerful steps by which evolution modulates enzyme activity to investigate the emergence of proteins at the dawn of protein evolution. The events of early protein evolution are clouded by the passage of time and by the very different environment in which life emerged compared to the one prevailing today. Here, too, Danny made seminal contributions. He experimentally demonstrated how small yet functional protein fragments, which likely preceded even the last universal common ancestor, might be genetically duplicated or fused to other proteins to create large, modern-day-like functional proteins [[18-22]]. In one of his last publications, Danny looked at the phylogenetic record to understand the timing of the so-called Great Oxidation Event. In this event, the Earth's atmosphere turned irreversibly from being almost oxygen-free to having substantial amounts of molecular oxygen as it does today. In a typically innovative and mold-breaking study, he demonstrated that the earliest progenitors of present-day oxygen-utilizing enzymes date back to the ancestor of all marine and terrestrial bacteria [[23]]. These findings place oxygen-utilizing progenitor enzymes almost half a billion years before the time in which most geological evidence suggests the Great Oxidation Event occurred. Like so many of Danny's studies, this one also demonstrated his virtuosity at asking the right question and finding the most elegant and convincing way to answer it. In this case, he used clues encoded in modern oxygen-utilizing enzymes to make inferences on events that shaped our biosphere some 3 billion years ago.
While the above highlights Danny's unique scientific contribution, to us and an entire generation of young protein scientists, Danny's mentorship, boldness in pursuing new ideas, and his boundless generosity in sharing his insights and time have been no less inspiring. Since the authors of this obituary have become principal investigators studying protein design, function, and evolution, our conversations with Danny and his research papers shaped our understanding of the most significant scientific challenges. Indeed, critical studies from both laboratories were inspired by his insights or done collaboratively with him. One of the main contributions that S.J.F.'s lab has made, based on Danny's insights, is developing a new and effective strategy for designing functional proteins by combining phylogenetic analyses with Rosetta atomistic design calculations [[24, 25]]. Together with Danny, we have developed general and automated methods that we and others have used to design enzymes, binders, and vaccine immunogens with superior stability [[17]], expression yields [[26, 27]], and activity profiles [[28]]. This strategy builds directly on Danny's insights on the stability-threshold effect and the potential to improve promiscuous enzyme activities [[13, 24]] and has been used by researchers around the world [[29]]. It is a shining testament to Danny's versatility and open-mindedness that he enthusiastically supported and participated in this line of computational research which differed from his main interests. In addition, research in A.A.'s laboratory on the function and evolution of multispecific proteins that are essential for cell survival was greatly inspired by Danny's discoveries [[30-32]]. For both of us, Danny was a key figure in shaping these studies through many discussions on our findings, suggesting possible interpretations and future research paths.
On the personal level, Danny was both a scientific leader who influenced many young scientists to study protein function and evolution and a true friend who was a part of our families. Over the time we have known Danny, we embarked on countless trips in Israel, Jordan, and other places where we extensively shared scientific findings, challenges, and personal life events. Danny's passion for science and his genius promoted discussions on various scientific topics. They inspired new research in our laboratories with students who felt equally comfortable discussing science with us as with him. He consistently amazed us with his passion for life and enthusiasm, always finding time for another meeting and adventure. His pleasant personality combining optimism with a wise sense of humor and open-mindedness won him many friends over the years. Danny's tragic and untimely death leaves us with many warm memories but with a huge gap that will be impossible to fill and reconcile. We are indebted to him for his generosity and are obliged to pass on his scientific passion, enthusiasm, and energy to the next generation of young scientists.
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.16019
Dan Salah Tawfik (1955-2021)—A giant of protein evolution
Mikael H EliasJames S FraserShina Caroline Lynn KamerlinWayne M PatrickColin J Jackson
EMBO Rep (2021)22:e53256https://doi.org/10.15252/embr.202153256
It was with great sorrow that we have learned of the untimely death of our friend, mentor, collaborator, and hero, Dan Tawfik. Danny was a true legend in the field of protein function and evolution. He had an incredibly creative mind and a breadth of knowledge—his interests spanned chemistry and engineering to genetics and evolution—that allowed him to see connections that the rest of us could not. More importantly, he made solving biochemical mysteries fun: He was passionate about his work, and his face lit up with joy whenever he talked about scientific topics that excited him (of which there were a lot). Conversations with Danny made us all smarter by osmosis.
Danny’s own evolution in science began with physical organic chemistry and biochemistry. His PhD at the Weizmann Institute of Science, awarded in 1995, was on catalytic antibodies under the supervision of Zelig Eshhar and Michael Sela. It was followed by a highly productive period at the University of Cambridge’s Centre for Protein Engineering, first as a postdoctoral fellow with Alan Fersht and Tony Kirby, and then as a senior researcher. Among his many achievements during his time in Cambridge was the demonstration that off-the-shelf proteins—the serum albumins—could rival the best catalytic antibodies in accelerating the Kemp elimination reaction due to non-specific medium effects. This work was an early example of unexpected catalytic promiscuity, and it sowed the seed for Danny’s later fascination with “esoteric, niche enzymology” that went far beyond convenient model systems.
It was also in Cambridge where Danny first realized the power of the then new field of directed evolution, both for biotechnology and for elucidating evolutionary processes. He and Andrew Griffiths pioneered emulsion-based in vitro compartmentalization. The idea of controlling biochemical reactions in separate aqueous droplets inspired emulsion PCR and next-generation sequencing technologies, whereas Danny used it to solve a long-standing problem in directed evolution; in vitro selection techniques had always been good at identifying ligand-binding proteins, but compartmentalization finally enabled the directed evolution of ultra-fast catalysts.
Danny returned to Israel in 2001 to join the faculty of the Weizmann Institute of Science where his scientific trajectory further evolved, diverged, and even “drifted”. He developed new methods for enzyme engineering and applied his evolutionary insights into de novo protein design efforts. In this context, Danny’s interest was always focused on how proteins evolve, particularly the connection between promiscuity, conformational diversity, and evolvability. His depth of understanding underpinned both applied research, such as engineering enzymes to detoxify nerve agents, and fundamental research, such as the evolution of enzymes from non-catalytic scaffolds.
Through it all, Danny retained his sense of joy and wonder at the “beautiful aspects of Nature’s chemistry”. This includes his discovery of an exquisite molecular specificity mechanism mediated by a single, short H-bond that enables microbes to scavenge phosphate in arsenate-rich environments. In recent years, he deciphered the biosynthetic mechanism of dimethyl sulfide, “the smell of the sea”, and homed in on the interplay between the evolution of an enzyme, its host organism, and environmental complexity. His insights into how the first proteins emerged caused tremendous excitement in the field. He established the roots of two common enzyme lineages, the Rossmann and P-loop NTPases, as simple polypeptides, and suggested ornithine as the first cationic amino acid. Prior to his death, he published the results of another tour de force: evidence that the first organisms to utilize oxygen may have appeared much earlier than thought.
His work impacted many research fields, and he won many significant awards. Most recently, Danny was awarded the EMET Prize for Art, Science and Culture (2020), informally dubbed “Israel’s Nobel Prize”. He was an active and valued member of the EMBO community, having been elected in 2009, and, until his passing, served on the Editorial Advisory Board of EMBO Reports.
Danny was also a superb science communicator. Both his research articles and reviews are a joy to read. What stood out just as much as his brilliance was his personality, as he embodied the Yiddish concept of being a true “mensch”. Danny was humble, was down-to-earth, and treated all his colleagues—including the most junior members of our research teams—as equals. He championed the careers of others, both those who worked directly for him and those who were lucky enough to be “just” his friends and collaborators. He believed in us even when we did not believe in ourselves, and he was always there to answer questions both scientific and professional. While he loved to share his own ideas, he would be just as excited about ours. Despite his own busy schedule, he always found the time to help others. He was also excellent company, with a great, very dry, sense of humor, and endless interesting stories, including from his own colorful life. In the days after his untimely death, an often-repeated phrase was “he was my best friend”. Danny’s former group members have gone on to be highly successful in both industry and academia, including more than 15 former doctoral and postdoctoral researchers who are now faculty. The network of researchers Danny has trained, mentored, or influenced is broad, and this legacy is testament to his qualities as both a scientist and a person.
Figure 1.
Dan Salah Tawfik (1955–2021)
Photo courtesy of Prof. Joel Mackay, The University of Sydney.
Danny was born in Jerusalem to an Iraqi Jewish family, and his Arabic Jewish identity was important to him. He believed strongly in coexistence and peace, and very much valued the Arabic part of his heritage. In his own words: “I am an Israeli, a Jew, an Arab, but first and foremost a human being”. He would often speak of the achievements of his children with immense pride. Danny also had a passion for being outdoors, especially climbing and hiking—when the best discussions were often to be had (Fig 1). One of the easiest ways to persuade him to come for a seminar, a collaborative visit, or a conference was to have access to high-quality climbing in the area. He passed away in a tragic rock-climbing accident, doing what he loved most outside of science. Our thoughts are with his partner Ita and his children, and we join the much broader community of friends, collaborators, and colleagues whose hearts are broken by his sudden loss.
https://www.embopress.org/doi/full/10.15252/embr.202153256
Dan Salah Tawfik (1955–2021)
Paola Laurino & Nobuhiko Tokuriki
Nature Chemical Biology volume 17, page930 (2021) Cite this articl
Dan Tawfik suddenly left us on 4 May, 2021. His scientific intuition led him to articulate, and solve, many key questions related to protein chemistry and molecular evolution. Although science, particularly for his students, postdoctoral fellows and colleagues, is dimmer after his loss, his legacy will persist.
Danny appreciated the complexity and simplicity of nature. He often referred to a quote from Charles Darwin: “…from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved”. Like the proteins that occupied so much of his thought, his scientific interests continuously evolved over his career. He was trained as an organic chemist and subsequently moved into biochemistry, enzymology, and directed protein evolution, then combining these passions to study the chemistry that underlies the evolution of biological molecules and systems.
Credit: Itai Belson, Photography section, Weizmann Institute of Science
Danny was a unique, visionary and brilliant scientist. He continually sought new questions to investigate. His ability to broadly and deeply comprehend scientific questions enabled him to quickly distil their core elements and turn these ideas into research programs for his laboratory and beyond. Science was his identity rather than his occupation, and at times it was an obsession. In his own words, “doing science was very natural for me”. Danny pioneered evolutionary biochemistry and he led the way to understanding many of the basic principles that underlie the processes of protein and enzyme evolution. He originated, explored and consolidated key concepts for protein evolution, such as the link between enzyme promiscuity, function–stability trade-offs, conformational dynamics and ‘evolvability’. He extended and applied those theories to study the evolution dynamics of many natural proteins, and the development of the technologies and approaches used to engineer enzymes and proteins including emulsion-based laboratory evolution, protein stability modulation for functional evolution, and neutral drift. Most recently, his work was centered around the origin of life and the emergence of primordial proteins. He demonstrated how complex protein structure could emerge from “simple yet functional” short proteins.
Danny produced a striking number of influential scientific publications while maintaining a relatively small lab group throughout his career. He led a strong and productive group, largely by investing inordinate amounts of time into discussions with his lab members almost every day. He was a humble and very approachable mentor who cared for, and deeply respected, those working with him. He instilled in each of us the idea that science should be pursued ethically, rigorously, and creatively, and that problems should be approached from different perspectives. The respectful way in which he engaged with his team facilitated broad discussions that could range from solving small technical issues to debating deep scientific questions and new ideas for future directions in the field. Research projects can also bring insurmountable obstacles and difficult times. On such occasions, Danny provided seemingly limitless time and unwavering support.
His enthusiasm for scientific problems was contagious, and as a result, many of us undertook research careers in academia or industry. He created a global scientific family that he continuously supported. Despite his extremely busy schedule, he was always available to chat about science and life with former lab members and frequently combined business travel with an extended visit to our respective institutions. His mentorship also extended to our own lab members, and he would generously offer his time and advice to them as well. He always maintained a wonderful humility and would engage in long conversations with virtually anybody, from professors to undergraduate students who he’d only just met.
On a personal note, Danny was a wonderful person to spend time with: intelligent, knowledgeable, curious, funny, cynical, kind and thoughtful. He appreciated and believed in diversity and equity in the research environment and, more importantly, in life. He especially supported those who came from different scientific, cultural and ethnic backgrounds and welcomed and integrated us into his group like family members. Naturally, many of us became close friends, both with him and with each other. He fostered deep and meaningful relationships within his lab, commonly inviting lab members and colleagues to his house where he would cook delicious food (in addition to his scientific accomplishments, he was a very talented chef). Visiting him in his home and interacting with his family was wonderful. Danny was a lovely father, and he was deeply proud of his children. During these dinners, as well as the everyday lunches in the Weizmann Institute of Science, he shared stories from his childhood, discussed politics, and talked of hiking and climbing spots. Danny loved nature and was particularly fond of the Israeli desert.
Science teaches us that matter and energy are eternal and dynamic. Life breaks free, moves, and transforms. It passes through one barrier after another. Nature does not know extinction, only transformation: nothing disappears. Over the course of his life, Danny embodied this principle, ever evolving, yielding ideas, questions, and principles most wondrous and beautiful. Danny’s impact in science will persist and his presence will never be lost.