OriginALS

Integrated Human Practices

It all began in the summer of 2017, the newly recruited iGEM-BGU team was tasked with choosing a topic for our iGEM project. Many ideas were proposed but one idea resonated with us. Liat Tsoran, one of our team members, told us her personal story. Liat’s father, Nir Tsoran, was diagnosed with ALS when Liat was only eleven years old. For seven years (longer than the average patient’s survival rate), Liat witnessed her father’s health, deteriorates from a fully functional adult to a man trapped inside his body.
Throughout his ordeal, Nir did not let his disease prevent him from being an exemplary father and advocate. He served as the CEO of IsrALS, an Israeli non-profit organization committed to supporting ALS patients, their families, and promoting ALS research in Israel. Nir took this budding non-profit and the very small Israeli ALS scientific community and turned it into an influential strong local movement.
Since her father’s diagnosis, Liat has been dedicating her life to understanding the disease and hopes, to one day contribute to finding a cure. Once we heard Liat’s story, the whole team enlisted to join her efforts. We suddenly understood that the “Ice Bucket Challenge” was not just a fun activity but a necessary step in bringing awareness to a devastating disease which has not received the exposure required to promote significant research for a cure.

The journey begins

One of our first steps when delving into this area of research was meeting with Efrat Carmi, CEO of IsrALS, who had inherited the position from Liat’s father. From this discussion we understood the gravity of this disease, how it decimates a person’s life in a rapid and irreversible way. How ALS research and awareness was, until recently, marginalized due to the rarity of the disease and the small size of the patients population. We heard about the challenges of finding a cure for a disease which is only 10% familial, leaving the other 90% of patients even further from a cure. From this important meeting we drew a few conclusions crucial to the development of our project: that there is a need for a general approach which will cover the whole patients population and the significance of a therapy which would lengthen patient survival and quality of life, regardless of the origin of the disease. Throughout this conversation we also understood the sensitivity of the matter to the patients and their loved ones. The necessity in exploring and presenting our ideas in a way that does not give false hope. These core principles guided us throughout our research and when delivering our message to ALS patients and the general public.

A therapy to all ALS cases

Next step was to thoroughly review available scientific information. Along with an in-depth review of the of the scientific literature we met with Dr. Adrian Israelson, PI of an ALS lab at Ben-Gurion university. Adrian described the budding interest in focusing on glial cells in ALS research. He has also described the unsuccessful attempts made to return the reactive Astrocytes to their healthy form. We identified that a focus on the microglia cells as relevant to our desire to develop a therapy applicable to all ALS cases, familial and sporadic alike!

if it ain’t broke, improve it!

At this point we focused our interest on the Microglia and Astrocyte cells. Through our reading we identified the NFkB pathway as a target for cytokine knockdown in Microglia. However, we still needed to figure out how to tackle the reactive Astrocytes. As currently there is no way to reverse reactive astrocytes state to their resting state. The only viable option seemed to be to kill the reactive astrocyte cells. With this idea in mind, we were reminded of the 2015 BGU-iGEM project, Boomerang.
This team used a double-plasmid system delivered by viruses in order to specifically target and kill cancer cells. The system answered many of our needs. It provided specificity by splitting the CasperCas9 enzyme and the gRNA components onto two different plasmids. We gave this plan an extra boost by choosing viruses which specifically infect only our target cells. At this point we had a concrete work plan! However, we still had reservations about approaching brain cells like cancer cells, unwanted cells we wish to kill. On top of this, we were concerned about suggesting the use of viruses in a therapy for humans.

justifying the risk

Luckily, we met with Dr. Perry Nisen, a member of the Board of Directors of Teva Pharmaceuticals. Dr. Nisen is an expert in neurodegenerative disease and a leader in the pharmaceutical industry. We presented our hypothesis and research plan to Dr. Nisen and then discussed our misgivings. An in-depth discussion regarding ethical dilemmas concerning genetic engineering, virus delivery, and the risk in killing central nervous system (CNS) cells led us to the following conclusions: Although genetic engineering is currently controversial, iGEM and Synthetic Biology aim to harness this technology for human advancements. Exploring these methods is the only way to make them safe and viable. We concluded that currently virus delivery is not ideal or accepted for drug delivery, however in the research phase it will give us a better chance of reaching proof of concept. Finally, although killing CNS cells may sound drastic, ALS is a fatal, aggressive disease. The benefits must be weighed against the risks. We believe that prolonging ALS patients’ survival indeed justifies this risk.

For and with the ALS community

From this point we were ready to enter the lab phase of our project. In addition, we began planning our human practice activities. As we were aware of how sensitive it may be to present preliminary research to ALS patients and their families, we decided against presenting our project to this community. Rather, we would show our support through volunteering and participating in the annual isrALS fundraising race. Still we felt strongly about promoting awareness about ALS and Synthetic Biology. We realized that science, specifically synthetic biology projects, can only be implemented efficiently if there is a public support. Therefore, the first step is to promote awareness and understanding of such a project. This is why we hosted “iGEM on the Bar”. We invited our peers, colleagues, and the public to an evening at a local pub, with a small entrance fee, where we presented our project and invited our guests to donate or join the annual ALS race. All proceeds from this event were donated to the ALS community.

embraced by the scientific community

As we mentioned previously, the community of ALS research labs in Israel was very limited until recently. Still, as this is a small country, the budding community is still rather small, yet impressive. We were touched by how this community embraced us when we began our project. Any lab we talked to was more than happy to help point us in the right direction, teach us new tools, or provide access to equipment. We were compelled to do something in return, so we organized the annual ALS Research Conference at the Ben-Gurion University of the Negev (our University). The conference was a great success! Not only did we hear from the leading experts in ALS research, we were able to present our project for the first time in a scientific setting. Our presentation received encouraging responses. The community seemed truly excited by our idea and the questions we received were not about the viability of the idea, rather they were insightful thoughts regarding research methods. Many researchers offered their inputs and assistance to aid us in proceeding with our project. One of these researchers, was Dr. Dinorah Friedmann-Morvinski‏ from Tel-Aviv University.

achieving a proof of concept

Around the time of convention, we faced a major lab roadblock. We were having trouble infecting our cells with the plasmids we had designed, due to their size and the sensitivity of the CNS cell lines. Without the ability to insert our plasmids, we had no way of implementing our system. This is when Dr. Friedmann stepped in. Dr. Friedmann heard about our struggles and offered a project-saving solution. Her research group works with plasmids which implement knockdown of genes in the NFkB pathway and delivers these plasmids with viruses. Dr. Friedman was instrumental in teaching us infection techniques and providing us with plasmids from her lab. This collaboration meant, that even if we did not succeed in implementing our designed plasmids before the competition, we would still be able to achieve a proof of concept.

Meeting the next generation of scientists

Our project would not have succeeded without our Human Practices. Our goals and implementation were all a result of involvement in the communities around us and sharing our ideas through discussions with experts. Science cannot proceed unaided and cannot succeed without public support. As a final gesture, we were delighted to host a group of high-school students in our lab. We had a great time explaining to them about iGEM, our project, and our lab. Although we ourselves as undergraduate students are only at the beginning of our scientific careers, it was wonderful to transfer the knowledge we have gathered to a new generation.