What's the Physiological Relevance? A Profile of Oded Rechavi

As a Professor in Molecular Biology at Tel Aviv University in Israel, it would be easy to assume that Oded Rechavi's career in science was written in his biology – his entire family are scientists or clinicians. His father, Gidi Rechavi, a well-regarded professor of hematology, won the Israel Prize 2020 in the field of medicine. But this was not the case.

Growing up, Rechavi always thought of his father as a medical doctor rather than a scientist. As such, research was not a regular topic at the dinner table in his household: "We didn't really talk about experiments, research or journals, so I didn't know that research existed as a profession." As he puts it, he was raised in an environment to produce scientists, but it affected him indirectly: "I couldn't control it."

Rechavi's first love was art and he speaks of it with fervour. After completing military service – mandatory for Israeli citizens – he traveled to Paris, immersing himself in the Parisian culture and exploring the local art galleries for six months. Upon returning to Israel, he was prompted by family members to consider studying at university.

"It's true that I was raised in an environment to produce scientists, but I guess it affected me indirectly. I couldn't control it."

After initially leaning towards a degree in psychology and philosophy, a relatively new course advertised in the University of Tel Aviv's brochure caught his interest: an interdisciplinary program in neuroscience. He commenced study in 2003 and – as he describes – was "sucked in" by the field of biology. The artistic flair remained, however, and in his second year of undergraduate study Rechavi presented an exhibition of his paintings.

During an undergraduate project, Rechavi found himself in the lab of the highly-regarded biochemist Prof. Yoel Kloog, where he also became acquainted with Dr Barak Rotblat. Rotblat says that, despite being at an early stage in his career, Rechavi was ambitious and did not shy away from proposing research ideas to the team: "I remember one of the first meetings Oded and I had with Yoel. Oded had an idea that the protein we were studying (RAS) can move from one cell to the other, and to use the interaction between immune cells and their targets as a system to test this idea. Yoel and I looked at each other and laughed because we were thinking that RAS might travel between cells, but we did not know how to test this!". Rechavi says that Kloog, who sadly passed away last year, was his role model – a true friend that treated him like he was his son.

"There are many connections between art and science, and different scientists have different motivations. I look at my career as an attempt to do creative things and express myself, similar to an artist."

After completing his PhD at Tel Aviv University, Rechavi embarked on a postdoctoral position within the lab of Oliver Hobert, a Howard Hughes Medical Institute investigator, at Columbia University, New York. Rechavi describes choosing Hobert as a mentor as being one of the best decisions that he ever made: "Oliver is incredibly smart and supportive, he'll tell you the truth to your face and has the best advice. I still run every professional decision that I make or think of making by him."

Rechavi had been in love with New York City (NYC) since he was a teenager, and the idea of living there had been a longstanding dream: "I used to go to NYC with my family fantasizing about jogging in Central Park and going to Knicks games." He chose to do his postdoc in NYC because, as the song goes, "if you make it there, you'll make it anywhere". Rechavi and his wife, who is a designer, loved their time in the city that never sleeps: "It’s a tough city to work in, but it’s worth it. The atmosphere, and the scientific scene, are incomparable.”

Something radical

Pursuing an academic career is not an easy feat, and an early career researcher faces a multitude of pressures and demands. Securing funding, achieving work–life satisfaction and contending with impostor syndrome are just a few examples. To thrive under such pressures, scientists often establish themselves in one particular field of research where they carve a niche, build a specialism and – quite often – stay in that space.   

When the opportunity arose for Rechavi to start his own laboratory at Tel Aviv University in 2012, he decided to paint outside of the lines. He wanted to create something unique and "radical" – quite literally – his lab is headlined as "the laboratory for radical science".

"I had the idea [for the headline] before I even had the lab," Rechavi says. "We want to try things that other people don't try – crazy and bold science. We strive to challenge dogmas and prove everyone wrong. That's the motto."

The Rechavi lab is probably best known for its work on transgenerational epigenetic inheritance, however its team members study a wide range of topics, which are sometimes completely unrelated to one another. What it lacks in focus it makes up for in creativity and innovation – it shapeshifts between a myriad of scientific disciplines, driven by its member's unique areas of interest, rather than where the obvious funding opportunities lie. How does this fair for recruitment? According to Rechavi, quite well: "When the lab started, it attracted people of the same mindset. People that are willing to be daring, take risks and know that they may have to try 10 different things until something works out." The lab now has 18 members.

Bruce Springsteen's lyrics from Dancing in the Dark: "You can't start a fire without a spark" are displayed on the research section of the lab's website. Fire in your belly – a true craving for discovery – are the prerequisites for thriving here it seems.  

Transgenerational inheritance

The pursuit of something radical is what led Rechavi to the field of transgenerational inheritance, which he first became interested in whilst working in Hobert's Lab. It is a notoriously controversial research space exploring mechanisms of heredity, specifically whether biological memories can be inherited across generations.

Acquired traits are not coded in your DNA (as most inherited traits are) – they are developed during your lifetime. Theoretically speaking, we should not be able to inherit acquired traits. Say you burnt your arm on the hob and it caused a scar to form on your skin. Your offspring would not be born sporting the same scar. That's because the scar has caused a change in the somatic cells, and only germline cells are able to transmit DNA to future generations. This is the Second Law of Biology.

Rechavi's interest lies not with DNA but with its cousin – small RNA. Small RNAs are non-coding RNA molecules that regulate gene activity via an array of different mechanisms in both the nucleus and the cytoplasm in response to changes in environmental stimuli.¹ The transgenerational epigenetic inheritance theory posits that the methods by which genes are turned "on" or turned "off" in this manner could perhaps be passed on to the next generation.

It's a phenomenon that is inexplicably tricky to study in humans, but a number of interesting occurrences throughout history have given weight to the idea. L.H Lumey's Dutch Hunger Winter Families Study found that descendants of the Dutch population that survived the famine of 1944–1945 had higher levels of low-density lipoprotein cholesterol, higher rates of obesity, schizophrenia and diabetes in adult life.² The famine had ended long before their time, but did the descendants still carry the scars in their biological makeup?

Rechavi's research on transgenerational inheritance focuses on the Caenorhabditis elegans (C. elegans) worm model, which he finds "irresistible", and is suitable for such experiments because of its short lifetime and the large number of genetically identical offspring each mother produces. Over the last decade, his laboratory has demonstrated that a number of different events, experienced by a C. elegans worm, can impact the physiology of their offspring.

Through a series of genetic experiments, the scientists discovered that inducing expression of the Flock House virus in C. elegans results in the production of small-interfering RNA molecules that essentially silence the viral genome. These molecules are extragenetic, and yet they are transmitted to the next generation of the worm, providing "vaccination" against the virus in the offspring.³ When starved, a number of small RNAs are induced in C. elegans that regulate genes implicated in nutrition, and these small RNAs are also expressed in the progeny for at least three generations.⁴ These studies are the first direct evidence that an acquired trait can indeed be inherited.

"There's a feedback mechanism that shuts down the inheritance after three to five generations. This feedback mechanism is small RNA-based, but there are genes that modulate the inheritance of these small RNAs that function as a timer. We named them MOTEK genes, which stands for modified transgenerational epigenetic kinetics, and means sweetheart in Hebrew – that was a sort of a joke that only Hebrew speakers would understand," Rechavi explains. In mutant worms where these genes are engineered to be defective, the transgenerational responses last for different periods of time, with some being present for hundreds of generations.

New rules for inheritance?

In a very recently published paper, Rechavi and colleagues show that, whilst at the population level an RNA response essentially shuts down after three to five generations, at the individual level, worms have different inheritance durations. These findings fall outside of the traditional rules of inheritance, and so, they created their own rulebook. Rechavi explains the rules: "[1]When you expose the worms to double stranded RNA or you start a silencing response, although the worms are genetically identical, some will assume a state that is supportive of RNA inheritance and some won't. [2] If you isolate each of these worms and look at their progeny, all the worms that they lay inherit a small RNA-based response in the same way."

He likens the third and final rule to the "hot hand" phenomenon. If you want to assess whether an inheritance response will continue or stop at the individual level, you look at the history of the lineage. Lineages in which responses have been silenced for multiple generations are more likely to continue the silencing, whereas shorter lineages are more likely to stop the response."

"These studies are very original on the one hand and scientifically sound on the other. I also think he [Rechavi] gets a kick from finding things that defy the current hype." – Barak Rotblat.

Studying transgenerational inheritance is an ongoing project for the Rechavi lab, and one that has led to a collaboration with neuroscientists, economists and linguists to explore how experiences perceived by neurons are transmitted from parents to the progeny. The researchers intend to explore whether such mechanisms are also at play in mammals.

An "accidental" exploration into ancient history

One of Rechavi's most recently published studies was conceived "completely by accident" on a retreat hosted by the University of Tel Aviv back in 2012.⁵ He found himself sitting next to the Biblical scholar Prof. Noam Mizrahi on the bus to dinner. They exchanged conversation, delving into the details of their current research projects and future aspirations. When Rechavi discussed his focus on the C. elegans worm model, Mizrahi’s interest was sparked.

He had been researching the remnants of the Dead Sea Scrolls, 25,000 fragments of parchment that were discovered mainly in caves around the archaeological site Qumran in the Judean Desert, trying to piece them together. Among the scrolls are the oldest copies of biblical texts which shed light on the history of Judaism and Christianity, containing collections of hymns, prayers and the earliest version of the Ten Commandments. Unfortunately, their historical significance was not a factor of consideration for the worms that made a meal from the scrolls, creating holes in the parchment, part of what makes their reconstruction a phenomenal challenge.

On the bus journey, Rechavi and Mizrahi pondered on how they could join forces and use modern biological techniques to piece the fragments together. The parchments are written on animal skin, and so they hypothesized that, should they be able to extract the ancient animals' DNA, they could apply next-generation sequencing methods to deduce which fragment came from which animal, creating a "genotype" fingerprint, and in turn, piece together the ancient puzzle.

And so, by complete chance, a project that would unite ancient history and modern biology was born. It would take a total of seven years to reach publication, and as Rechavi explains, required a lot of energy: "We needed funding and to convince the authorities that this experiment would be possible without causing damage to the scrolls. It took more than two years to convince them and to conduct calibration studies amongst other experiments to demonstrate that it was possible to extract DNA from very small amounts of the scrolls."

Another string of accidents led to several collaborators joining the team, including Prof. Mattias Jakobsson of Uppsala University, an expert on ancient DNA analysis, who Rechavi happened to be introduced to whilst giving a talk in Uppsala University. "It was like in the film Ocean's Eleven, we collected people that could contribute their own strengths which is really a beautiful thing," Rechavi says.

The team generated over 2.6 billion sequencing reads, and in doing so, learnt a lot about the scrolls and their history. The genetic evidence allowed the researchers to distinguish between fragments that originated from different animals of the same species. If the fragments belonged to the same scroll, the likelihood is that they were from two different sheets. Furthermore, two of the fragments found were genetically different from all the other samples, indicating that they are unrelated to the scrolls.

Rechavi explains that, for him, the major highlight of this work was proving their hypothesis was true: "You can extract enough authentic DNA from pieces that are over 2000 years old and use it to learn about the relationships of the different fragments. Aside from the fact that it's cool, it shows how interdisciplinary science can have real value."

This was just the beginning of Rechavi's exploration into ancient history. The team sampled only a selection of the 25,000 fragments, so there is still a lot of work left to be done. In the short period of time since the paper was published, he has been contacted by a variety of researchers that are keen to collaborate on future studies to further unearth the secrets of the Dead Sea Scrolls, and learn more about the extracted ancient animal DNA. "I could never write a grant eight years ago explaining what we are going to do. This project is a living thing – sometimes you just can't plan," says Rechavi.

Woodstock bio: A new era for science conferences?

Rechavi is a prominent figure – perhaps somewhat of a celebrity – in the world of Twitter science, boasting 18.5k followers on Twitter.* He has a humorous presence online, and you might be familiar with his tagline, "What's the physiological relevance?" in which he indirectly mocks the notion that all scientific research must have a reason, a "physiological relevance" behind it. Even the American rapper MC Hammer is acquainted with his work.

Rechavi explains that such stardom (or “notoriety”, in his words) is, again, the result of an accident. "I never thought I would be “big” on Twitter. When I first joined [Twitter] in 2016, I didn't know how to use it," he says. "I just started telling stupid jokes and – surprisingly – people responded well to it." He praises the social media site for being a "great platform" to learn about novel research and the mindset of other scientists from across the world.

In 2014, Nature conducted a survey of over 3,500 researchers across 95 different countries to enquire about their social media use. Twitter was used regularly by 13% of the survey respondents, with over half of those individuals stating that they utilized it to follow conversations relating to research. Fast forward six years – online communities such as Academic Chatter and Open Academics are thriving, connecting scientific researchers from across the globe.

Rechavi also believes Twitter presents a solution to a prominent issue in the scientific community – cliques. "When you go to scientific meetings and you don't know anyone, you just meet with the same people that have been attending for years. I think that the new connections people form on Twitter are really breaking down hierarchies and allowing science to be free and more enjoyable," he says.

It was this love of new connections and forming friendships that led to Rechavi adding conference producer to his resume, after he organized "The Woodstock of Biology" event earlier this year.

"On a Friday night, I posted a tweet saying that I would be happy to organize a conference for the people that I like on Twitter. I thought it would be nice to know these people in person, and I have a lot of friends on Twitter that I have never met.”

When he awoke the next morning, Rechavi was greeted with hundreds of positive responses and decided that he would pursue organizing the conference. The Woodstock of Biology was born, and it was to be "different" from a traditional scientific meeting, he says, "I wanted no hierarchy, I wanted no selection – everyone who wanted to present and signed up on time was allowed to. You were also only allowed to present unpublished work, which is very unusual."

Talks were restricted to 10-minute slots, and rather than having a strict agenda, each presenter had to choose a "walk up" song that would be selected at random and, when played, would signal to the scientist that it was their turn to present. "We wanted to surprise them and keep the speakers on their toes, so that they wouldn't disappear or go drink coffee," Rechavi says. 

He adds, "It was like a big party. I enjoyed it tremendously, and I think others did too." If Twitter testimonies are anything to go by, The Woodstock of Biology conference was very well received.

Deep emotion is apparent in his voice when he discusses one attendee's story – who is kept anonymous for the purpose of this article. "He spoke of how he was sick of some aspects in science, of the usual hustle, trying to get funded, being forced to publish and stay focused. He had lost interest and wanted to quit or make a change. Whilst on stage he said that the conference had saved him. He now saw the light, and it gave him the energy and motivation to continue in science. It was an unbelievable moment."

The COVID-19 global pandemic has not impeded Rechavi's plans to run a second The Woodstock of Biology conference sometime in the future, when it is safe to do so. If anything, the apparent success of online conferences during this time adds further credence to his philosophy that there are other – perhaps better – ways of sharing and interacting with research than tradition tells us.

The soul of an artist

Rechavi is doing science refreshingly differently. He is a shapeshifter of sorts, meandering his way through a successful career in science in a fashion that rejects tradition, changing what it means to think like a scientist, "disrespecting hierarchies" and drawing inspiration from art, life and the people that surround him – in addition to books. A voracious reader, he recently enjoyed Sylvia Plath's The Bell Jar, and is now reading Objectivity by Lorraine Daston and Peter Galison. "I read many different things. Ideas will come from somewhere unexpected, and I like to be inspired by different people that have very different point of views and life experiences," he says.

When they asked me what I wanted to be I said I didn’t know. "Oh, sure you know," the photographer said. "She wants," said Jay Cee wittily, "to be everything." - Sylvia Plath, The Bell Jar.

The unpredictable nature of Rechavi's research provokes a sense of enticement and mystery to science that, as the final presenter at The Woodstock Bio conference alluded to, has perhaps been lost, or buried over time. Rotblat describes his friend and former colleague Rechavi as having the "soul of an artist", which simply begs the question: What will he create next?

Oded Rechavi was speaking to Molly Campbell, Science Writer for Technology Networks.

*Correct as of September 3 2020.

References:

1.     Stuwe E, Tóth KF, Aravin AA. Small but sturdy: small RNAs in cellular memory and epigenetics. Genes Dev. 2014;28(5):423-431. doi:10.1101/gad.236414.113

2.     Lumey L, Stein AD, Kahn HS, et al. Cohort Profile: The Dutch Hunger Winter Families Study. International Journal of Epidemiology. 2007;36(6):1196-1204. doi:10.1093/ije/dym126

3.     Rechavi O, Minevich G, Hobert O. Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans. Cell. 2011;147(6):1248-1256. doi:10.1016/j.cell.2011.10.042.

4.     Rechavi O, Houri-Ze’evi L, Anava S, et al. Starvation-Induced Transgenerational Inheritance of Small RNAs in C. elegans. Cell. 2014;158(2):277-287. doi:10.1016/j.cell.2014.06.020.

5.     Anava S, Neuhof M, Gingold H, et al. Illuminating Genetic Mysteries of the Dead Sea Scrolls. Cell. 2020;181(6):1218-1231.e27. doi:10.1016/j.cell.2020.04.046.