Job Opportunity: Research Assistant (ImmunoSENS)

SENS Research Foundation (SRF) is hiring a Research Assistant for our Research Center (RC) located in Mountain View, CA. SRF is an exciting, cutting edge non-profit dedicated to transforming the way the world researches and treats age-related disease.

We are seeking a Research Assistant in our ImmunoSENS group for a project geared toward developing therapeutic interventions to rejuvenate immune clearance of senescent cells. This project involves working with human blood samples and primary human cells. This is a full-time position.

Qualified candidates will have a BS or MS in the chemical/biological sciences and substantial bench experience. Duties will include mostly bench work in a small team-oriented environment.

Candidates should have experience in WBC purification, culturing primary cells, quantitative real-time PCR, western blot, immunofluorescence, ELISA, micro plate readers, FACS analysis, and data analysis. Candidates with experience in 2nd and 3rd generation lentivirus system are particularly encouraged to apply.

Interested candidates should submit a cover letter and resume to [email protected].

We offer an excellent benefits package including paid vacation and sick leave, fully covered health insurance (inclusive of dependents), an FSA program, and a company matched 401(k) plan, all of which is offered after a 90-day introductory period. SENS Research Foundation is an equal opportunity employer.

The position is available now and will be filled as soon as the qualified candidate is found. Salary is commensurate with job title.

Job Type: Full-time
Salary: $48,000 to $50,000/year

SRF Research Center Immunologist Application Form

UPDATE: This post has been filled.

Immunologist

SENS Research Foundation (SRF) is seeking a full-time researcher for a Scientist position to work at our Research Center located in Mountain View, California. The position is to lead a new intramural research project geared toward performing translational research studying aging as it relates to the immune system, with a possibility of developing a new therapeutic. This is a collaborative effort between SRF and the Campisi Lab at the Buck Institute for Research on Aging, located in Novato, CA. The collaboration allows the researcher to work with two institutions at the forefront of the anti-aging field, and allow for mentorship from experts in the field. The successful applicant will work with, and be guided by, senior researchers at both SRF and the Buck, and as such this position is available to new PhDs as an alternative to doing a Postdoc (or a 2nd postdoc). The position offers the opportunity for upward mobility into a more senior, PI level position. Leading a team at SRF is an exciting career opportunity in a team environment where everyone is dedicated to discovering new treatments for the diseases and disabilities of aging.

Required Experience

  • PhD or equivalent doctoral degree in the chemical/biological sciences
  • Expertise in the innate immune system

Desired Capabilities

  • Independent planning and project design
  • NK cell knowledge or experience
  • Proficient at the bench and with data analysis
  • Management / mentoring experience
  • Comfortable working in a small team environment and with collaborations with other institutions

Compensation

SRF is proud to offer a competitive salary of $65-75,000/yr for this position, which includes paid vacation and sick leave, fully covered health insurance, inclusive of dependents, an FSA program, and a company matched 401(k) plan offered after a 90-day introductory period. SRF is an equal opportunity employer.

Interested candidates should apply by email to Dr. Matthew O’Connor, taking care to include all of the information and documentation listed below.

Applicants moving onto the second phase of the application process will be contacted by email by a SRF representative for an interview.

Application Information

Contact Information:

  • Last Name / Surname
  • First Name / Given Name
  • Email Address
  • Phone Number
  • Full Mailing Address

Academic Information:

  • Graduate Institution
  • Program or Department
  • Graduation Date
  • First available date to begin position

Documents:

Attach documents in PDF, DOC or DOCX format.

  • CV or Resume.  Please limit your CV or resume to a maximum of 2 pages. Highlight any prior laboratory or research experience. A brief 1- or 2-line description of your specific contribution to each research project is particularly helpful. For instance, the statement “created the expression construct that allowed us to determine protein localization” quickly clarifies your role in the project.
  • Cover Letter.  A cover letter describing your knowledge of SRF’s damage repair approach to aging as well as your experience in immunology; please limit your letter to one page.

A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis

SENS Research Foundation Research Center

Principal Investigator: Matthew O’Connor
Research TeamAmelia Anderson, Carolyn Barnes, Angielyn Campo, Anne Corwin, Sirish Narayanan

Many diseases of aging are driven in part by the accumulation of “junk inside cells:” stubborn, damaged waste products derived from the metabolic processes particular to specific cell types. The accumulation of these wastes disables the cell type in question and leads to their dysfunction; when, after decades of silent accrual, a critical number of these cells become dysfunctional, diseases of aging characteristic of that tissue erupt. For example, atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke. In other organs, the accumulation of damaged molecules inside vulnerable cells drives Alzheimer’s and Parkinson’s diseases, as well as age-related macular degeneration.

Dr. O’Connor’s team have identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood. If effective, these small molecules could serve as the basis for a groundbreaking therapy that would prevent and potentially reverse atherosclerosis and, possibly, heart failure.

Research Highlights:

A lead compound was identified following evaluation of data from human blood sample tests in conjunction with computer modeling to predict the likely behavior of rationally-designed molecules. Preliminary testing has indicated performance consistent with enhanced activity relative to the existing family of compounds: specifically, the candidate molecules exhibit selective targeting of toxic cholesterol byproducts, with significantly reduced affinity for native cholesterol. A patent application for this lead compound and others to be derived from it has now been submitted.

The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays. SRF has recently acquired a new robotic system to run the assay, which our in-house engineer, Anne Corwin, is now working to set up and program; the end result will be an increase in throughput that allows more rapid testing of more molecules.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

SENS Research Foundation Research Center

Principal Investigator: Amutha Boominathan
Research Team: Bhavna Dixit, Carter Hall, Caitlin Lewis, Matthew O’Connor, Martina Velichkovska

Mitochondria are the tiny cellular “power plants” in our cells, which take energy from our food and convert it into a form that can be used to power the cell’s energy-intensive processes. Like other power plants, they generate waste in the process – in this case, free radicals – which over time damage mitochondrial DNA. As a result, a small but rising number of our cells get taken over by such dysfunctional mitochondria as we age. These damaged cells in turn export toxic molecules to far-flung tissues, contributing to Parkinson’s disease, age-related muscle dysfunction, and other conditions.

The MitoSENS goal is to achieve a grand engineering solution to the problem of accumulation of cells with these mutation-bearing mitochondria: allotopic expression of functional mitochondrial genes. Allotopic expression involves placing “backup copies” of all of the protein-coding genes of the mitochondria in the cell’s nucleus. From this “safe harbor”, the copied genes can then direct the cell’s machinery to produce engineered versions of the missing mitochondrial proteins and deliver them to the mitochondria. With their full complement of proteins restored, mitochondria can resume producing energy normally, despite lacking the genes to produce them on their own.

Research Highlights:

In 2016, the MitoSENS team achieved a major breakthrough in successfully demonstrating efficient replacement of the missing mitochondrial ATP8 gene in cells from a human patient with an ATP8 mutation, restoring their ability to produce energy using the most efficient pathway.

After significant work to extend 2016’s breakthrough to other genes, the team discovered that an established method already widely used in biotechnology could also be applied to enable significantly more consistent production of allotopically-expressed protein.

To test this novel method more broadly, the MitoSENS group first briefly allotopically expressed each of the thirteen vulnerable mitochondrial genes via a transient loop of DNA located in the cytosol. Versions of the genes engineered the new way produced a great deal more RNA (the “working copies” of the gene that the cellular machinery uses to make protein) than the same genes engineered in the way that all previous investigators have used.

All thirteen of the genes engineered in this new way were able to produce actual protein, versus only a fraction of the conventionally-engineered genes. This milestone achievement is being prepared for publication in a scientific journal as of this writing, and tests are now underway to verify that all proteins thus expressed are properly incorporated into the mitochondria’s energy-production system.

The team has compared performance between ‘traditional’ and novel systems for producing allotopic ATP8 in cells derived from FVB mice. These mice bear a minor but significant mutation in ATP8 that causes functional problems, e.g., a tendency to poorly metabolize incoming blood sugar after a meal. The cells engineered using this novel method produced significantly more ATP8 protein than those engineered the conventional way – and it is important to note that in this experiment, the new genes were actually cemented into the nucleus and expressed from there, thus mimicking the goal for human MitoSENS therapies. The allotopically-expressed protein works as intended when using the improved system: it enters the mitochondria, incorporates properly into the energy-producing machinery, and significantly enhances these cells’ ability to survive when they are forced to rely on the mitochondria’s primary energy-generation mechanism.

Next, the MitoSENS team plans to demonstrate efficacy in living, breathing mice – specifically,  Maximally Modifiable Mice (MMM) from the SRF funded work at ASC. The new MMM-derived mouse model will have the allotopic ATP8 construct engineered into their nuclear genomes from conception, but will have mitochondria (and thus mitochondrial DNA) derived from FVB mice, with their mutant ATP8 gene. This work, in conjunction with behavioral studies to be performed in collaboration with the Brand lab at the Buck Institute, is expected to prove that the allotopic gene actually functions in vivo, restoring the mice’s ability to generate cellular energy efficiently.

Enhancing Innate Immune Surveillance of Senescent Cells

Buck Institute for Research on Aging & SENS Research Foundation Research Center

Principal Investigator: Judith Campisi
Research Team: Abhijit Kale (Buck Institute), Amit Sharma (SRF-RC)

When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue (the “senescence-associated secretory phenotype” (SASP)). The charge sheet against senescent cells has now expanded into a remarkable litany of the diseases of aging.

Multiple studies have now, on a more encouraging note, documented that “senolytic” drugs and gene therapies that destroy senescent cells exert sweeping rejuvenating effects in aging, both in laboratory animals and animal models of multiple diseases of aging. But in theory, senolytic therapies shouldn’t be necessary. The body’s immune system is on continuous patrol against senescent cells: our natural killer (NK) cells, recognize senescent cells as abnormal, bind to them, and release substances that trigger the senescent cells to self-destruct.

In a Foundation-donor-funded collaboration between Dr. Judith Campisi’s lab at the Buck Institute and the SRF Research Center, this project seeks to answer the critical question of why senescent cells accumulate with age, and what might we do to enhance immune surveillance and elimination of these cellular saboteurs?

Research Highlights:

Dr. Campisi has found that about ten percent of senescent cells are resistant to being killed, even by fresh NK cells, suggesting that these resistant cells are the ones that escape immunosurveillance and accumulate in aging tissues. Her research team and other scientists have developed preliminary data suggesting mechanisms whereby senescent cells can make themselves invisible to NK cells, thus protecting themselves from destruction.

The Buck-SRF-RC collaboration is now seeking to drill further down into these questions and test possible means to intervene in the process. The Campisi lab is looking into further elaborating the biology of one of senescent cells’ two self-protective mechanisms, and also testing a potential role for another kind of immune cell (macrophages) in defending the body against senescent cell accumulation.

At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process, and will begin testing two potential therapeutic targets identified in the Campisi lab. The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially “aged” by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them for the first time to observe any direct effects of aging on NK cell senolytic activity. The team is also developing an algorithm for the SRF-RC’s automated microscope imaging system to rapidly analyze stained plates of cells for quantitative analysis of senescent cell-killing ability — a job hitherto done by laborious human visual microscopy.

Functional Neuron Replacement to Rejuvenate the Neocortex

Albert Einstein College of Medicine

Principal Investigator: Dr. Jean Hébert
Research TeamHiroko Nobuta, Joanna Krzyspiak, Alexander Quesada, Marta Gronska-Peski, Jayleecia Smith

Of all the challenges in cell therapy, replacement of neurons in the neocortex is both the most important (the brain being the seat of consciousness and identity) and perhaps the most formidable. Only recently have any researchers succeeded in integrating new neurons into this area of the brain. Moreover, the vast majority of transplanted cells in these cases have failed to survive, and the few survivors have achieved only limited function and integration into existing circuits.

SRF is now supporting Dr. Jean Hébert’s work to advance two innovative strategies to address different aspects of the challenge. First, Dr. Hébert’s team will transplant neuronal precursors (from both mice and humans) along with precursors of the blood vessels needed to nourish new neurons, in order to enhance their survival and integration. Second, because new neurons will be needed throughout the aging neocortex but transplanting neurons throughout the entire tisssue would be extremely invasive and risk injury to a tissue we cannot afford to damage, the AECOM team will engineer microglia (which, unlike neurons and their precursors, are highly mobile cells) to disperse widely from the site of transplant and then be reprogrammed into cortical projection neurons at their destination. From there, the team will characterize the integration of the transplanted microglia-cum-neurons into host circuits of converted neurons derived from our engineered transplanted microglia, and determine whether depleting host microglia enhances these processes in different models.

Glucosepane Crosslinks and Undoing Age-Related Tissue Damage

Yale University

Principal Investigator: David Spiegel
Research Team: Prof. Jason Crawford, Nam Kim, Venkata Sabbasani, Matthew Streeter

The long-lived collagen proteins that give structure to our arteries and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to tissue collagen by sheer chemistry, and if not quickly reversed these initial links will in turn bind adjacent strands of collagen, reducing the range of motion of the tissue like the legs of runners in a three-legged race. As a result, these tissues slowly stiffen with age, leading to rising systolic blood pressure, kidney damage, and increased risk of stroke and other damage to the brain.

It is currently thought that the single most common of these Advanced Glycation End-products (AGE) crosslinks is a molecule called glucosepane. A rejuvenation biotechnology that could cleave glucosepane crosslinks would allow bound arterial proteins to move freely again, maintaining and restoring the elasticity of the vessels and preventing the terrible effects of their age-related stiffening. SRF has provided funding to the Yale GlycoSENS group for several years now, in order to develop tools necessary for enabling the development of glucosepane-cleaving drugs.

Research Highlights:

The Yale group’s first major milestone – the first complete synthesis of glucosepane itself – was a sufficient tour de force to earn publication in the prestigious journal Science. In 2018, they were able to scale up this pilot-level method to produce glucosepane in quantities useful for industrial production, and also to synthesize three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are now working on two more such variants. They have also used their synthetic glucosepane to develop glucosepane-targeting antibodies capable of labeling glucosepane in aging tissues, which they are now working up into a monoclonal antibody for mass production that will be compatible with human metabolism and will allow researchers to track the effects of potential glucosepane-cleaving drugs.

Finally, and most excitingly, they have now identified a lead candidate glucosepane-cleaving biocatalyst, and completed the evaluation of seven significant variants and their AGE-breaking mechanism. Today, work continues on synthesizing pentosinane (another common AGE crosslink) and additionally on the AGE-related compounds iso-imidazole and 2-aminoimidazole.

Maximally Modifiable Mouse

Applied StemCell, Inc.

Principal Investigator: Dr. Ruby Yanru Chen-Tsai

The CRISPR/Cas9 gene editing system has the ability to make precisely-targeted changes in the genetic sequence – a clear strength of the platform – but is limited in its lack of an obvious delivery mechanism. It’s reasonably easy to use CRISPR/Cas9 to modify individual cells, but there is no known (or clearly-foreseeable) way to deliver the system to human tissues in vivo while still retaining strong precision and without the risk of either silencing or mutating introduced or non-targeted genes.

Moreover, CRISPR/Cas9 is really only able to make relatively small changes to an existing gene. That’s great for correcting small but catastrophic mutations in existing genes, or rendering genes with a toxic gain-of-function inoperable — but it’s not much use for delivering the new genes that will be necessary to take advantage of it for delivery of rejuvenation biotechnologies.

The Maximally-Modifiable Mouse project aims to overcome this problem by allowing us to make use of a powerful gene insertion system (the integrase) used by phages — viruses that target bacteria as their hosts. The mycobacteriophage Bxb1 catalyzes precisely-targeted, one-way insertion of even very large genes into the host genome. Unfortunately, mammals lack the genetic “docking sites” that this integrase targets. To enable the development of models of diseases of aging and the rapid testing and eventual human delivery of rejuvenation biotechnologies, SENS Research Foundation has been funding Stanford gene therapy spinoff Applied StemCell (ASC) to create a line of Maximally-Modifiable Mice (MMM). The MMM will have two of the needed docking sites engineered directly into their genomes, which will then be ready for the insertion of new therapeutic transgenes at any time during the lifespan.

Research Highlights:

Currently, ASC is testing the ability of the system to deliver and integrate convenient test genes into the mice’s cells in vivo. They will then test the expression and functional protein production of those genes. We are especially excited by the potential to use this technology to both develop better models in which to test the allotopically-expressed mitochondrial genes that our in-house Mito team has been testing in cells, and to deliver those genes and actually test them in such mice.

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