My research focuses on characterizing rare cell populations from bone marrow and peripheral blood with a specific emphasis on their progressive dysfunction in the aging process. Much of this work centers around hematopoietic stem cells (HSC). HSCs are residents of the bone marrow and give rise to all blood cells. The age-associated dysfunction of HSC and their progeny is a hallmark of an aging phenotype. The study of primary cells from the bone marrow presents several technical hurdles, ranging from techniques for cultivation outside of the body, to optimizing target cell harvesting, enrichment, and characterization. These challenges are compounded when we consider that there are subtle, yet often significant differences, in the behavior of blood cells between species. One of my favorite projects at Ichor involves optimizing the detection of rare engrafted donor cells in recipient mice, which is an important part of understanding the effects of transplanting donor cells to restore hematopoietic homeostasis in aged animals. There are many different models that can be used to track donor cells which only require a small quantity of peripheral blood for analysis. The donors in these models typically have a different phenotype from the recipient (e.g. GFP expression or unique surface antigens). This allows for donor and recipient cells to be distinguished in downstream analysis, enabling engraftment to be tracked over time. Flow cytometric analysis is a common (and my preferred) way to quantify the number of donor cells that are circulating in recipient blood. Not only can we track basic engraftment, but these cells can be further characterized post engraftment by looking at key surface markers, which can shed light on their function and activity after transplantation.

My research at Ichor is focused on engineering an antibody-like protein scaffold into targeted and highly specific therapies. What does that mean, exactly? The next time you’re watching TV and a drug commercial pops up, take a look at the name of the drug – if it ends with ‘-mab’, it’s what’s known as a monoclonal antibody (mAb). Since the first mAb therapy, muromonab, gained FDA approval in 1986, over 500 different mAbs have been approved or are being investigated for a myriad of diseases. Antibody treatments have very specific mechanisms of action, usually making them highly efficacious drugs with minimal side effects. They are often described with a ‘lock and key’ model – antibodies will bind tightly to their specific target once it is presented, with minimal off-target effects. Their biggest downside is cost – complex, full-length protein structures are costly to produce and are highly unstable. Antibodies are inherently fragile and contain tightly woven molecular structures which must be kept intact for full functionality. Prolonged storage, freezing and thawing, and temperature changes or exposure to room temperature will quickly and irreversibly denature antibodies, rendering them useless. This, combined with the complexity of production, makes antibody therapies expensive options for patients in developed countries, and often inaccessible to third-world and developing areas^[1][2]. In the US, for one year of treatment (excluding hospital fees), the average mAb is $96,731, and $142,833 for cancer mAb treatments, with many exceeding $200,000^[2]. Currently at Ichor, I’m developing a cost-effective protein scaffold which may be a suitable replacement for some antibody therapies. It has been shown to have antibody-like specificity for engineered target sequences, is incredibly heat and pH stable (Tm ~ 102C, pH stable 4-10), can be made orally-bioavailable and survive the GI tract, is easily expressed in E. Coli, and can be produced for a fraction of the cost of mAbs^[3]. Importantly, the exterior of our protein can be modified to recognize specific sequences without affecting its larger structure or stability – similar to mAbs. Our immediate goal is to prove efficacy against any therapeutically relevant targets, but we eventually hope to use RPtag’s uniquely stable properties in targeting novel anti-aging pathways which have been largely unreachable by mAbs, such as the GI tract.

We still have a long development road ahead of us, but we hope to one day be able to provide people with inexpensive and highly effective therapies for life-threatening diseases.

1. Elmore, S. NIH Public Access. 35, 495–516 (2007).

2. Hernandez, I. et al. THE AMERICAN JOURNAL OF MANAGED CARE ® Pricing of Monoclonal Antibody Therapies: Higher If Used for Cancer? 24, (2016).

3. Derosa, J. R. et al. RPtag as an Orally Bioavailable, Hyperstable Epitope Tag and Generalizable Protein Binding Scaffold. Biochemistry 57, 3036–3049 (2018).

My research at Ichor involves applying various biophysical methodologies towards small-molecule drug discovery. Numerous diseases originate from pathogenic protein-protein interactions (PPIs)^[1]. Disruption of these pathogenic PPIs with small molecules can be an effective therapeutic modality for disease^[1].

Effective characterization of a small molecule’s effect on a given PPI requires many experiments. Executing numerous experiments requires scalable quantities of biologically active protein. Researchers frequently produce human proteins in E.coli because E.coli can provide protein in large quantities, but this is not always the case. E. coli lack the machinery necessary to make certain human proteins properly, resulting in inactive product^[2]. This limitation forces researchers to settle with studying small pieces of the protein instead. These small pieces (commonly called fragments) can behave very differently than their native, full-sized counterparts, which can adversely impact research efforts when produced fragments are not physiologically relevant.

Ichor has developed a proprietary protein expression system which frequently allows for barriers commonly encountered in protein production to be overcome. Ichor’s ability to produce full-sized human proteins at scale using this technology enables extensive and otherwise inaccessible insights into certain PPIs. For the past several years the company has applied this technology in the study of various pathways associated with cancer and cellular senescence. My current work involves repurposing this platform for the study of other PPIs thought to be involved in the onset and progression of aging and age-associated diseases.

Citations:

[1] Scott, D.E., Bayly, A.R., Abell, C., and Skidmore, J. (2016). Small molecules, big targets: drug discovery faces the protein–protein interaction challenge. Nature Reviews Drug Discovery 15, 533–550.

[2] Rosano, G.L., and Ceccarelli, E.A. (2014). Recombinant protein expression in Escherichia coli: advances and challenges. Frontiers in Microbiology 5.

My previous work at Ichor examined the claims that administration of buckminsterfullerene in an olive oil solution leads to mammalian life extension. Buckminsterfullerene (also known as C60), is a molecule composed of 60 carbons which form a soccer ball like spherical structure. Carbon molecules link to each other in a matrix throughout the molecule, which give it interesting characteristics such as the ability to absorb free radicals and to appear as a red, wine-like color in solution. During our initial investigations, however, we became concerned with the quality of C60 that was being provided to people on the open market, specifically through online vendors. In a series of studies, I investigated the quality, health effects, and characteristics of C60 which being sold. The results of this research are being finalized and will be submitted for peer-review this year.

Beyond work with specific molecules like C60, Ichor is working to target each of the hallmarks of aging with specific interventions. The primary focus of my graduate work has been advancing Ichor’s flagship intervention for age-related macular degeneration (AMD). AMD is characterized by lysosomal dysregulation, driven by the accumulation of indigestible retinoid-based waste products that clutter the lysosome and inhibit native degradative processes. Our approach to this problem is an enzyme augmentation therapy (EAT) which introduces a recombinant enzyme that is capable of degrading the indigestible waste products in the lysosomes of affected cells. Our early proof-of-concept work on this program was published in late 2018 and demonstrated that this approach is efficacious in a mouse model of AMD. Since then, my emphasis has been on formulating the enzyme to produce a clinical candidate suitable for use in patients.

In it, you will hear his thoughts about the Undoing Aging conference, the state of funding in rejuvenation research, thoughts about the next steps in implementing therapies, the future of the SENS foundation, and Aubrey's personal regimen.

Quoted from the Insilico website:

"Our Mission is to extend healthy longevity through innovative AI solutions for drug discovery and ageing research. We aspire to be a leader in the field of deep learning for drug discovery, personalized healthcare, and anti-aging interventions."

Let us know if you have any questions for Alex in the comments below.

His upcoming gene editing research on dogs is aimed at reversing ageing with the goal of moving this to humans in approximately 8 years!     You can read more about it in this article.

You can also watch this YouTube video where Dr. Church speaks about the delivery of 45 gene editing therapies, all targeted at reversing age-related disease. 

He's also the co-founder of Nebula Genomics, which empowers people to contribute to genetic research while dramatically reducing the cost of genome services to make it affordable for everyone! 

The interview is scheduled for next Friday the 15th February, let us know if you have any questions in the comment section below 

Brian helped found the Calorie Restriction Society International, and has been its president for over twenty years. He has published a book on calorie restriction and longevity, with Lisa Walford, The Longevity Diet, as well as numerous articles on aging and life-extension. He recently became president of the Society for Age Reversal in order to help advance research into very near-term solutions to the problem of aging, and to make existing treatments of age-related maladies more widely available.

Synopsis

What has happened to American democracy? No Popes in Heaven is a political thriller with biting commentary about what has gone wrong with the world's ideal government. A major pharmaceutical company has developed a drug to slow aging but the long clinical trials required to bring it to market are just that: too long to be profitable. Operating with political maneuverings that would make Machiavelli blush, the Big Pharma company conceives of a different course of action brilliant, lucrative, and dangerous. But as its tactics spin out of control, the curtain is pulled back on the worst of Washington's machinations: big money, back room deals, betrayals, and political campaigns that leave the voters behind. No Popes in Heaven is a dark, humorous story that not only entertains but shines a new and different light on the question of why our American democracy is failing. The author wields a sharp sabre and no one – not the politicians, the lobbyists, the consultants or the press – is spared.

Let us know if you have any questions for Hal in the comments below!

SENS is part of our Longecity affiliate lab program and this is sure to be an interesting discussion about current research projects and future ambitions. We last interviewed Dr. O'conner 5 years ago where he talked about the MitoSENS mitochondrial research project.

Here's Dr. O'Connor's Bio from the SENS website:

Matthew was awarded his Master's degree at Northwestern Medical in 1999 for his work studying behavioral neuroscience in aged rodents. In 2005, at Baylor College of Medicine he received a PhD in Biochemistry for his work on proteins that regulate human telomeres. Postdoctoral research includes work at UC Berkeley on muscle stem cells and aging. Since 2010, Dr. O'Connor has headed up the MitoSENS project at the research center in Mountain View, California. His research is focused on "allotopic expression" of mitochondrial genes where his team is engineering mitochondrial genes to be expressed from the nucleus and targeted to the mitochondia. Since 2012 Dr. O'Connor has had broad oversight over many areas of research at SRF. Matthew O'Connor is passionate about performing basic research to combat the diseases and disabilities of aging.