New Science March 2024 Updates

Mar 31 2024

Some updates to share from this February + March –

Welcome to the most recent New Science fellows!

Mike Ferguson is a biologist and engineer (BS Cell and Molecular Biology from Michigan, MS Biomedical Engineering from Boston University) working on growing human blood vessels in the lab to unlock replacement tissue/organ therapies. From a young age, his sole motivation in life has simply been "making people live longer". He believes replacement tissues/organs will be helpful in this endeavor.  Mike spent 3 years working in a stem cell/developmental biology lab growing organoids and studying various ways that people were trying to make replacement tissues/organs. Realizing the need for a way to grow human blood vessels in the lab to unlock this dream, he pursued an engineering degree, believing that engineering tools would be required to solve the blood vessel problem. He has built his own lab to manufacture "microfluidic" devices, which are needed for his work, going so far as making cheap versions of expensive lab equipment to do this. Mike likes when biologists and engineers work together. He believes in a developmental biology approach to tissue engineering - growing tissues, rather than trying to artificially piece them together.

Mike is developing a microfluidic device and associated tools that enable one to grow "real" perfusable and transplantable human blood vessels in the lab. The technology is unique in that the blood vessels are formed using the same process that occurred when you were an embryo. Having previously demonstrated that the microfluidic technology can be used to grow scaled up tissues with perfusable human blood vessels, he is currently working on making the technology more mass producible and user friendly. Assuming he can raise the required funding, he plans on transplanting the blood vessels he is growing into rats to demonstrate the clinical potential of the technology.

Samarth Jajoo is a third-year undergraduate at UC Berkeley studying Computer Science. He is passionate about using machine learning methods to model biophysics and runs the BioML seminar series at Berkeley to create an active community in the field. Previously, Samarth worked on developing software for vaccine design at PopVax, optimizing tele-operated robots at Prosper, and contributing to web-based IDEs at Replit. 

As a New Science fellow, Samarth is working in Sergey Ovchinnikov's lab at MIT, where he is building ML models for protein folding that operate by simulating each amino acid as an agent. These models provide interpretability, and could also offer insights into protein dynamics and the biological process of protein folding, despite being trained solely on static crystal structures. Additionally, Samarth is exploring the use of evolution strategies to sample diversely from existing protein folding models, which could lead to better results with significantly reduced computational requirements compared to current state-of-the-art methods.

Katya Osipova is a postdoc at Harvard University working in the field of evolution and genomics. She is broadly interested in how evolution and natural selection shape phenotypic diversity, bridging the gap between genomic changes and phenotypic variation by combining computational  and experimental approaches. She is especially interested in extreme phenotypes observed in animals, specifically unlikely metabolic and behavioral adaptations that could give insights into mechanisms of human diseases. Katya majored in chemistry at Moscow State  University in Russia and completed her PhD in evolution and bioinformatics at the Max Planck Institute in Germany where she worked with large-scale genomic and transcriptomic data sets to find insights into the evolution of extreme metabolic adaptations in hummingbirds. Outside of research, she does everything that is somehow related to music: from listening to producing and recording trashy covers.

As a New Science fellow, Katya will look into how metabolic systems evolve under thermodynamic constraints in the Informatics  group.  She will start with a comparative analysis of eukaryotic metabolic networks, leveraging publicly available genomic data. Next, she plans to use examples of extreme metabolic adaptations to build predictive models of pathways' energetic outputs. Finally, Katya plans to use genome editing in cell lines and organoids to generate novel living systems with defined energetic and metabolic properties.

2024 New Science fellows - welcome to Mike, Samarth, and Katya!

In other news, our infra tooling experiments are well underway. Along with forming the backbone of our project tracking for each fellow, we also explored using Linear for several book discussions, and have arranged several meetups among fellows online through Gather.town, virtually, as well as in person where feasible. We’re excited to share more about the results of our fellows’ projects soon!

best,
–Sasha

(Correction from the previous newsletter - Scott Berger was awarded the ARCS Foundation scholarship rather than ASCB graduate student award.)

New Science January 2024 Updates

Jan 31 2024

Sasha here — thank you (reader of this update) for being interested in the activities of New Science, and more generally, in exploring how to create an institution (hopefully many institutions!) of science that will achieve the goals and needs of an ever-changing world of humans, the technologies we develop, and our built + natural environments. 

As of the start of the year, I’m very grateful to continue the work that Alexey has done to get New Science to where it is today, in the role of executive director. 

This month, we: 

• Spent time delineating our deliverables for the quarter and year. One among them is creating a playbook for our fellowship programs and remote-first sharing + project management stack. This will include open resources on how we use Distill, Linear, and Watershed on the infra side. We look forward to feedback on how others use these tools.

• Onboarded several new collaborators + contributors to the New Science team

• Soft-launched our research website (research.newscience.org) — many improvements coming very soon.

Our theme of the year (which arose in consilience between our fellows and internal team) is shipping. Our focus area for the quarter is largely executing on this tooling + collaborations and we expect to have prototypes to share within Q1.

This transition point also seems like a fitting point to review what we’ve done at New Science the past year. Some high points from there —

Our footprint is growing! Collin - Maple Ridge; Dylan, Scott and Julie - Stanford; Diana - Berkeley; Michael - Toronto, Yasmeen - Montreal; Avadhoot - Pune; Adam, Benjamin, Daniel, and Alex - Boston; and Alex - NYC.

In 2023 we expanded beyond the SF Bay Area and Boston science ecosystems and supported fellows located in New York City (Rockefeller), Canada (Toronto, Montreal and Vancouver) and India (Pune). We’re looking forward to hosting more opportunities like our last ‘Demo Party’ (fellow retreat) to gather face-to-face.

Receiving well-deserved accolades, our one year fellow Scott Berger became an ARCS Foundation Scholar, Avadhoot Jadhav was accepted to begin PhD studies at Karolinska, Adam Strandberg was accepted to PhD studies at Harvard, and Benjamin Chang won a Rhodes Scholarship to Oxford. We could not be prouder and wish them the best for their adventures in these new places.

New starting this year, we have a ~quarterly snail mail update as well (which does not fully overlap the above). If you’re interested in receiving it, please fill out the form here (friends.newscience.org/updates) and we will send it to you.

We will have more information on most of the areas above, namely our progress to date, in February + March and are looking forward to sharing + getting your input. Until then! ❄️

—Sasha 

---

Hi everyone,

It's been a huge privilege for me to spend the last several years studying metascience and to run New Science. We've supported many dozens of young scientists with fellowships, grants, and mentorship, published metascience research I'm incredibly proud of, and learned a great deal about how science really works ourselves.

However, having been focused on metascience since 2018, I've come to realize it's time for me to take a break. Next, I’ll be in Boston learning physics — say hi if you’re around!

In light of this, Sasha Targ, New Science's Head of Research is now going to be the Executive Director, assuming the leadership of the organization and its mission. While I am a complete scientific ignoramus, Sasha has a PhD in bioinformatics from UCSF, is a real scientist, and is otherwise better than I am at almost everything. I'm excited to see what she has prepared for science and for New Science in the coming years!

Cheers,

Alexey

New Science September 2022 Updates

New grants and projects.

Organization

• Our one-year fellowship begins. Julie Chen and Scott Berger will spend the next 12 months in Stanford and Boston. They will probe the causal role of methylation in aging and explore the evolution of multicellularity (which has popped up independently at least 25 times)! More details soon.

• Last week, we hosted a Demo Day in Cambridge. Summer Fellows presented their work and got feedback from local scientists. This event marks the official end of this year’s program. 🎻

  • Each fellow wrote an essay and technical report about their work. We’ve made the former publicly available on our Substack and website. Full-length research reports will be published soon.

  • Two summer fellows remain in Cambridge and will continue their projects. Avadhoot Jadhav, in Hidde Ploegh’s lab, will continue building a “universal immunotherapy” using nanobody-peptide fusions. And Diana Leung remains with Xu Zhou; her project explores how cells coordinate and change behaviors when cultured near other cells.

• We made a $10,000 grant to Dylan Husmann at Stanford University to study tunable mutation rates.

• We made a $35,000 grant to James Heathers to develop software that will semi-automate detection of spurious statistics in research papers.

Kian presents his summer research at the Demo Day.

Projects

• We’re building a marketplace to connect scientists with philanthropists. If you have an ambitious idea for a research project but don’t know where to go for funding, please email us. We’ll help you write a 1-page proposal — with only minor requirements — and will consider funding your idea.

• We’ve published several pieces on the Substack lately. We think you’ll enjoy:

  • This history of the Rockefeller Institute’s Natural Sciences division, and how they spearheaded the mid-century revolution in molecular biology.

  • An essay on cell culture and (missing) context in experiments.

  • An essay on scientific ‘style,’ and how it went missing from our modern journals.

  • An upcoming piece on 20th-century pioneers. Keep an eye out! 👀

    • If you have an essay idea about science or metascience, please email us.

Interesting Jobs

• Arcadia Science always has compelling job openings. Applications are still open for their Entrepreneur-in-Residence program.

• Lorentz Bio is looking for a Director of Biology to join their founding team.

• Jakob Voigt’s Open Ephys (short for open-source electrophysiology) is hiring. They want to make the future of scientific instruments equitable and open. 

  • “Join us to work on high-performance open-source tools that read from and write to the brain. We are looking for an electrical engineer for firmware development, hardware design, and integration with custom ASICs. You will have the opportunity to propose and develop complete projects and will be working on tools that push the boundaries of neuroscientific discovery over the next decade. These tools will be used by thousands of scientists around the world, from those at elite institutions to labs that were previously priced out of the scientific conversation. For inquiries contact jpn@open-ephys.org.”

---

Stay Frosty,
Niko & Alexey

Reversing 1.5 Billion Years of Evolution

I’m building a free-living chloroplast to dissect the origins of multicellular life.

This is Part 3 in our New Science research series, where our Fellows explain the visions behind their work. Two additional Fellow essays, not sent via email, are available to read on our website. This, our last post in the series, was written by Kian Faizi.

---

“We are not made up, as we had always supposed, of successively enriched packets of our own parts. We are shared, rented, occupied… the colonial posterity of migrant prokaryocytes, probably primitive bacteria that swam into ancestral precursors of eukaryotic cells and stayed there…

I like to think that they work in my interest, that each breath they draw for me, but perhaps it is they who walk through the local park in the early morning, sensing my senses, listening to my music, thinking my thoughts.”
— Lewis Thomas, The Lives of a Cell

Plants weren’t the first to figure out photosynthesis, that careful dance of chemistry that harnesses sunlight to make our food and air. That honor belongs to microbes that first appeared 3.5 billion years ago, in the earliest known days of life on Earth. Some of them, called cyanobacteria, learned to split water into hydrogen and oxygen, and thus created our oxygen-rich atmosphere.

And then, about 1.5 billion years ago, something peculiar happened. A free-living cyanobacterium was engulfed by a larger eukaryotic cell in a phenomenon known as endosymbiosis. That bacterium escaped destruction and became a permanent resident — a cell living within another cell.

Soon, both parties realized they had stumbled upon a mutually beneficial arrangement. The larger, eukaryotic host siphoned food and energy from its photosynthetic guest; in exchange, it offered it shelter from the outside world. The cyanobacterium eventually lost its ability to live independently, handing off regulatory control to the eukaryote in a series of gene transfer events. It became a chloroplast: a specialized compartment that endowed the host with the ability to photosynthesize. All plants, in turn, descended from this single cell.

This transition from free-living cyanobacterium to integrated organelle was a landmark event in evolutionary history. An earlier event led to the creation of mitochondria.

Yet as momentous as endosymbioses are, the precise details of how they arise are still murky. There is much that we stand to learn by reverse engineering the process — but it won’t be easy. Scientific tools are limited, and deciphering this story, obscured by billions of years of complex coevolution, is akin to untying a Gordian knot.

I’m conducting a series of experiments aimed at reversing and reconstructing the chloroplast’s strange and fascinating history. The results could yield new insights into the evolution of multicellular life.

Modern endosymbiotic theory gained widespread acceptance in the 1980s, thanks to the work of Lynn Margulis, its principal champion and “vindicated heretic”. Her 1967 paper, On the origin of mitosing cells, weathered dozens of rejections before it was finally published. It’s now considered a watershed classic. 

Before Margulis, studies into the origins of chloroplasts and mitochondria were driven principally by the work of a few intrepid scientists who made careful observations — and persisted in the face of ridicule. The earliest known mention of endosymbiosis comes from an 1883 article by Andreas Schimper, a German botanist. In On the development of chlorophyll granules and colored bodies, he acknowledged the similarities between cyanobacteria and chloroplasts, before quietly adding a footnote:

“If it should definitively be confirmed that the plastids in egg cells [of plants] are not formed anew, then their relationship to the organism containing them would be somewhat reminiscent of a symbiosis.” (p. 112, footnote 2, emphasis added)

By 1905, the concept had been formalized in essays by the Russian botanist Konstantin Mereschkowski. In On the nature and origin of [plastids] in the plant kingdom, he outlines an endosymbiotic theory that comes astonishingly close to our modern insights. To his more influential contemporaries, though, his ideas were “too fantastic for present mention in polite biological society.” Ultimately, his work did not reach the mainstream — in part because it was overshadowed by his legacy as a serial rapist of children, who often evaded capture by fleeing to new countries.

Mereschkowski’s proposed tree of life, detailing two endosymbiotic events for the origins of nuclei and chloroplasts; the latter hypothesis is widely accepted today. (The theory of two plasma lineages as the foundation of symbiogenesis, a new principle for the origin of organisms, 1910).

American biologist Ivan Wallin argued for an endosymbiotic origin to mitochondria in the 1920s. To support his claim, he carried out a series of audacious experiments aimed at isolating and culturing mitochondria ex vivo. He claimed to have succeeded, but his results later proved irreproducible. Perhaps unsurprisingly, he too found little support among the scientific establishment of his day.

Things began to change as biologists developed new tools in the 1960s. Early genomic analyses crucially showed that chloroplasts contain their own DNA. Electron microscopy yielded the first detailed structural comparisons between chloroplasts and cyanobacteria. Unlike her predecessors, Margulis arguably prevailed thanks to this new experimental evidence.

Today, scientists have a greater palette of technologies to draw from than ever before. We can probe, modify, and dissect living things in ways that were previously impossible. Modern DNA editing, for example, allows us to engineer both the chloroplast and nuclear genomes as we desire; some labs are using these tools in attempts to recreate synthetic endosymbioses. 

All this gives rise to a daring question: Can we restore chloroplasts to a free-living state by re-endowing them with the genes that they’ve lost over 1.5 billion years of evolution? Even incremental progress towards this goal would yield important biological knowledge. As we work to wrestle back control over the organelle, we’ll uncover how the cell cycle, metabolism, and gene regulation are shaped by the interaction of host and endosymbiont. In liberating a chloroplast, we’ll be forced to unravel its complex evolutionary history using active experimentation and tinkering, rather than theoretical musings. To paraphrase Feynman, we should create a free-living chloroplast so that we may understand it.

During my New Science fellowship, I isolated chloroplasts from cells of the green alga Chlamydomonas reinhardtii using established methods. I’m carefully tweaking the chloroplasts’ environment to see which chemicals can support their metabolism in vitro. My first goal is to better understand how to make viable chloroplasts without any genetic engineering.

In the future, I intend to rewind evolutionary history by moving genes that were lost to the host over the last 1.5 billion years back into the chloroplast. In doing so, I aim to provide the first demonstration that chloroplast-derived, nuclear-encoded genes can be successfully repatriated without disrupting their function. I’m currently testing an existing method for inserting DNA into the chloroplast genome. Soon, I’ll compile a list of “high confidence” genes to be relocated. This may require the development of new computational approaches that can screen candidates by mining a combination of sequence data and the published literature.

These efforts will bolster our understanding of chloroplast function and phylogeny. In the future, they may even make it possible to engineer a new, free-living cell using an organelle as a starting point. What will this liberated chloroplast teach us — about its evolutionary history and the meaning of life itself? It’s time we find out.

Edited by Niko McCarty

---

Thanks to Lev Tsypin, Adam Strandberg, John McCutcheon, Sasha Targ, and Alexey Guzey for feedback on this essay.

Cite this essay:

Faizi, K. “Reversing 1.5 Billion Years of Evolution.” newscience.org. 2022 September. https://doi.org/10.56416/720qud

Towards a Universal Immunotherapy

Harnessing the immune system with protein engineering.

This is Part 2 in our New Science research series, where our Fellows explain the visions behind their work. This post was written by Avadhoot Jadhav.

---

Pathogens constantly spread, infect, and evolve. Lower respiratory tract infections and diarrheal diseases remain amongst the world’s top five leading causes of death. More than 6 million people — a conservative estimate — have died from COVID alone and new variants continue to emerge. Despite the threats that pathogens pose, we have limited tools to design drugs to fight them. Indeed, drug discovery remains a lengthy, costly, difficult, and inefficient process. In the COVID19 pandemic, nature is (kind of) winning — vaccines and antibodies help, but it is hard to keep up with an evolving virus.

Mother Nature can serve as a source of inspiration for drug design. The human immune system has its own unique method to keep pace with evolving pathogens. And, no matter how virulent a pathogen is, the human species has so far managed to adapt and (largely) survive.

It is thanks to proteins in our blood, called antibodies, that we can swiftly shut down dangerous invaders. With protein ‘tips’ of a flexible design, antibodies can “see” different structural features in a pathogen’s proteins. Upon binding to a viral invader or other pathogen, the antibodies signal and recruit various immune components, such as effector cells (a type of white blood cell), to eliminate infected cells.

Although we have gained some knowledge of how the immune system operates, the sheer complexity involved in its adaptive behavior is not easy to understand. But imagine if we could replicate this process synthetically. I propose a therapeutic strategy to do so, using protein engineering.

Physicians and scientists have made many attempts to manipulate the immune system. Vaccination and passive immunization are two examples, and both have been wildly successful, with millions of lives saved.

By exposing your body to a weakened version of a pathogen, or just a piece of a pathogen, one can train the immune system to produce antibodies that help fight that pathogen when it is first encountered in the wild. Despite the success of vaccines in tempering the COVID19 pandemic, there is already evidence of enhanced transmissibility and reduced vaccine effectiveness against emerging variants of concern, including Delta and Omicron. Current vaccines also have a narrow target range.

Moreover, a slow vaccination drive tends to increase selection pressure on the pathogen, leading to the emergence of more infectious variants. Current vaccines cannot keep up with new variants, and revamped generations of vaccines are constantly required. There are also psychological and logistical limits to how often people can be vaccinated, and we are still collecting data about these vaccines and immune-related adverse events.

At Caltech, Pamela Bjorkman has developed a mosaic-nanoparticle based vaccine that covers a broad range of targets, including variants of concern. Still, it can only prevent new infections once vaccine-driven immunity has built up, which takes time; it cannot deal with established infections.

Passive immunization is one alternative to vaccines — people are given antibodies that recognize the pathogen in question. But monoclonal antibodies, while efficacious, are expensive. Regeneron’s two-drug cocktail for COVID19 costs around $1,250 per infusion, according to Kaiser Health News. Monoclonal antibodies also must be kept cold, so as not to lose their efficacy. Even minor changes in a target virus’ protein structures can reduce the antibody’s effectiveness. That is why we still need a sustainable, cost-effective therapy with broad target specificity.

---

Two years ago, I was studying drug resistance in malarial parasites (as a part of the iGEM IISER Pune Team). It was then that I realized how structural changes in a viral protein, caused by mutations from drug-driven selection pressure, can be a root cause of therapies losing their efficacy. Naturally, I wondered: If shifting proteins can evade antibodies and cause this problem, maybe they can also provide a solution. After all, if nature has managed to devise an adaptable approach for keeping up with new pathogens, why can’t medicine do the same?

Proteins are modular in nature and are composed of domains, which are independently folded regions within a protein. Such modularity enables functional protein domains to be joined together synthetically or genetically, with the goal of altering their function to modulate the immune system. The therapeutic efficacy of a protein of such a design can be enhanced by choosing fusion partners that selectively target particular cell types or receptors.

Nanobodies — the smallest immune recognition modules derived from a unique class of antibodies found only in camelids — serve as the perfect functional building blocks to create such fusion constructs. They can recognize antigens, they are easy to produce and — equally important — they are cheap to make. Nanobodies show exquisite specificity, they are structurally stable, and they are capable of modulating immune responses.

At New Science, I am using protein fusions to develop a pan-coronavirus therapy.

Antibodies have two functions: they recognize antigenic proteins, and they recruit immune components. Immune evasion occurs when small structural changes in the antigenic protein render the antibody unable to recognize it. To overcome this problem, I built a computational algorithm that uses crystallographic structures of various protein-binding partners, such as receptors and antibody complexes, to generate a library of peptides, or small proteins, that can bind at many distinct sites on the viral protein’s surface.

My summer plan, from here, is simple. I took my computationally designed peptides — each of which recognize a site on the coronavirus' spike protein — and attached each of them, individually, to nanobodies that recruit different immune components to selectively eliminate infected cells.

Unlike monoclonal antibodies, which “see” a single structural feature on a virus, my approach can theoretically address any emerging variants of a viral pathogen. Changes in the virus’ antigenic protein, acquired by mutation and selection, should not result in resistance or impact the peptide cocktail's function because the designed peptides target several distinct sites across the protein’s surface. While resistance can easily develop against a single peptide or antibody, a range of peptide-nanobody fusions, each recognizing a distinct epitope, would be far more challenging for a virus to evade.

After assembling the peptide-nanobody fusions, I will test them in mice to see if they are effective at preventing or treating SARS-CoV-2 infections.

Are there limitations to my approach? Side effects may occur, as is the case for any other new drug. But I don’t know. This project is in its early stages, and any fusion proteins would go through rigorous, years-long testing, much like other therapies.

If this project works as intended, we will have developed a tool that can harness the immune system in completely new ways. It should be possible to selectively target, label, or destroy any cells we desire (be it SARS-CoV-2-infected cells or cancer cells), based on the antigens that are expressed on the surface of those cells. Most importantly, this type of therapy is inherently modular — built by fusing bits of proteins together — and should thus enable us to deal with any new or emerging pathogens. Only time will tell, and I’ll update soon with my progress.

Edited by Niko McCarty

---

Thanks to Alexey Guzey, Sasha Targ, and Hidde Ploegh for reading this.

Cite this essay:

Jadhav, A. “Towards a Universal Immunotherapy.” newscience.org. 2022 September. https://doi.org/10.56416/591plq