A Surrealistic Take on Genomics

A Surrealistic Take on Genomics

How would the late Surrealist artist, Salvador Dalí, view his genome? I suspect that the artist, who had a flair for painting things in midair as cats and water seemed to hover nearby, would have been fascinated by not only the concept of genomics, but the widespread human view of it.

Consider one of his famous works, The Persistence of Memory (1931). All the iconography oozing from this work can’t be discussed in a few hundred words. So, let’s just home in on the most memorable elements of the painting – the clocks. Dalí once called those clocks the “camembert of time” (camembert is a delectable soft cheese that could theoretically be good as donut filling).

The iconic melting clocks communicate that our perception of time is not solid or concrete; it is fluid and ever changing. However, to many people time will always remain solid because that is how they uncritically perceive it. If I were to bet my camembert-filled donut, I would say Dalí would view his genome as he did time. But many people perceive it as concrete and static: One gene equals one inheritable trait; mutation X causes disease Y. The early work of Gregor Mendel and others may have unwittingly set the stage for this kind of genetic determinism. However, scientists have demonstrated that the genome is vastly more complex, engrained with redundant elements, buffeted by environmental changes, and unable to fully explain our physiological identity at any given moment or across time (Weiss, 2018).

Your genome simply does not paint the complete portrait of you or your health. First, it is only predictive, and only to some relative degree. People harbor mutations that “should” confer horrible outcomes that never materialize due to genomic mysteries or lifestyle choices. It would seem like the mutation is just hitching a ride in the genome. Second, we could all have many different genomes existing throughout the body, not just the one reported in the test results. Third, the DNA could have picked up phantom mutations during sequencing that were not present in the actual sample. Hitchhiking mutations, multi-genomes and phantom mutations – what great subject matter for a Surrealist artist!

Test results from a set of identical twins serve as yet another example of the fluidity of our genetic understanding of ourselves (Argo and Denne, 2019). Although a team of researchers from Yale University deemed the genomes of twin sisters to be identical (99.6% based on raw data), the twins received very different readouts/interpretations from a genetic testing company, perplexing the twins AND the researchers. Different reports from four other genetic testing companies also failed to agree, even for the same individual. Perplexing indeed!

If Salvador Dalí viewed our perception of genetics/genomics the same way as time, how would he represent this in his artwork? Would he have painted melting DNA that seemed to keep dividing to resemble a fractal or genomic reports that morph into different objects? Would there be phantom DNA? Who knows, we could spend years discussing the possibilities. What is certain is that trying to grasp a static understanding of genetics/genomics to define our health will not lead to the precision medicine promise of the right medical treatment at the right time. We need to listen to the voices that are emerging to break the engrained perception that our identity or future resides in our DNA.

 

References

Argo, C. and Denne, L. (2019, January 18). Twins get some ‘mystifying’ results when they put 5 DNA ancestry kits to the test. CBC News. Retrieved on January 22, 2019 from https://www.cbc.ca/news/technology/dna-ancestry-kits-twins-marketplace-1.4980976.

Weiss, K. M. (2018). Genetic Pointillism versus Physiological Form. Perspect Biol Med, 61(4), 503-516. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30613033. doi:10.1353/pbm.2018.0060

 

Using Proteomics to Make a Rash Decision

Using Proteomics to Make a Rash Decision

Oh dear…what is that? Seeing (and feeling) a rash-riddled arm at 2 o’clock in the morning can be alarming. And turning to Dr. Smartphone Google adds even greater urgency to the fear: A rash can reflect a large number of conditions, from very serious to very mild. Even legit doctors have a tough time deciding which is which.

For example, it turns out that psoriasis, atopic dermatitis and contact dermatitis all present similar symptoms, which can make getting an accurate diagnosis – and treatment decision – difficult at best (Wang et al., 2017). A team of researchers from MedImmune, Mount Sinai Medical Center and Rockefeller University decided to try and fix that problem by testing the feasibility of developing a non-invasive test to differentiate between the different skin conditions and get the right individualized treatment sooner (Wang et al., 2017). Though previous genomic and transcriptomic analyses of skin biopsies have been informative, the team reasoned that proteomics may provide a better “real-time view” into the skin issues.

To put their hypothesis to the test, the researchers used SomaLogic® technology to measure the levels of proteins in serum samples from patients that had psoriasis, atopic dermatitis or contact dermatitis. Compared to healthy individuals, the researchers found 66 proteins that changed significantly in one of the three disease states. In other words, each type of rash could be diagnosed based on different protein changes. Interestingly, the researchers did find similar protein changes common to all three conditions, suggesting some shared biology.

As exciting as this news is that there is a possible basis in protein changes for making a definitive test for determining to determine the identity of the rash – and treat it effectively – is just beyond on the horizon, the researchers caution that the work is still very preliminary. But it does suggest a future where the rash decisions of Dr. Smartphone Google are less likely to make things scarier than they are.

 

References

Wang, J., Suarez-Farinas, M., Estrada, Y., Parker, M. L., Greenlees, L., Stephens, G., . . . Howell, M. D. (2017). Identification of unique proteomic signatures in allergic and non-allergic skin disease. Clin Exp Allergy, 47(11), 1456-1467. doi:10.1111/cea.12979

 

Hitchhiking to a Better Understanding of the Link Between Genomics and Cancer

Hitchhiking to a Better Understanding of the Link Between Genomics and Cancer

How much is too much? According to author Douglas Adams, the answer to all life’s questions is 42. It seems to work as an answer in any situation, such as “How many lemon curd-filled donuts are too much for me?”

“How much is too much?” is a good question to ask even in genomics. For example, how many mutations are too much and will give me cancer? In this case, however, “42” may not be universally correct.

The conventional – and logical – understanding of the link between mutations and cancer centers around the notion that once a cell has acquired enough mutations in key genes it will lead to a cancerous tumor. But is this really correct? Two research groups have recently provided evidence that will challenge your perception of the “logical” genomic galaxy (Martincorena et al., 2018; Yokoyama et al., 2019). Don’t panic and grab your towel!

The two teams set their sights on the esophagus, particularly the layer of cells that lines it, to better understand the underpinnings of cancer development. Not too surprisingly, both groups noted that the number of mutations increased with age and promoted cell proliferation. But they also noted several peculiar observations.

First oddity: Martincorena et al. reported that the cells lining a healthy esophagus possessed more mutations in cancer-associated genes than human skin cells, though fewer mutations overall. (This difference in overall rate is not surprising when you consider that skin experiences a lot of exposure to UV light, which directly causes mutations in DNA.) They also saw that the healthy esophaguses carried about 200 mutations per cell in young adults and over 2000 per cell in older adults. Yet, no cancer of the esophagus was detected in these people. Yokoyama et al. also saw an increase in mutations in older populations.

The second oddity noted had to do with the genes most often mutated in healthy esophaguses, which happen to be from a defined group known as the “NOTCH family.” These genes code for critical proteins that resemble contorted chains bedazzled with various modifications (Hori, Sen, & Artavanis-Tsakonas, 2013). The types of modifications present can dramatically change the way NOTCH proteins relay important messages to surrounding cells. These lines of communication are vitally important for embryo development, determining the fate of stem cells, suppression of cancer, promotion of cancer, etc.

Both research groups noted that the mutations found in the NOTCH genes are known to drive cancer growth. But cancer was not detected in the individuals carrying the “driver mutations.” Obviously, something beyond the gene is at work here.

Face it, our genomic galaxy is bizarre. The further into it we get, the more bizarre it gets. With the complexity of genomics, we may never truly know how many or what exact mutations will definitely cause cancer (though maybe 42 will be the answer in a few cases). Hang on to your towels as we continue to hitchhike through the human genome.

 

References

Hori, K., Sen, A., & Artavanis-Tsakonas, S. (2013). Notch signaling at a glance. J Cell Sci, 126(Pt 10), 2135-2140. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23729744. doi:10.1242/jcs.127308

Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., . . . Jones, P. H. (2018). Somatic mutant clones colonize the human esophagus with age. Science, 362(6417), 911-917. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30337457. doi:10.1126/science.aau3879

Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., . . . Ogawa, S. (2019). Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature, 565(7739), 312-317. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30602793. doi:10.1038/s41586-018-0811-x

 

The Proteomics of Face Transplants

The Proteomics of Face Transplants

How do others identify you? The simplest answer may reside in what others use to recognize you, your face. In fact, people may use your face to get a putative synopsis of you and make judgments accordingly (Rifkin et al., 2018). So much for the old saying of not judging a book by its cover.

What would happen if you somehow lost your face to injury or disease? Would you lose your identity? No, you would still be “you,” at least as you know yourself. But how others perceive you would likely change, usually in a negative direction. Rude or uncomfortable stares are inevitable and this unwanted attention can be a source of great duress.

Truly a feat of modern medicine, face transplants offer a new hope to individuals who experience tragic events that robbed them of their own face. In a recent publication from a face-transplant team, the authors stated that as many as 40 of these miraculous surgeries have been performed (Kollar et al., 2018). They also highlighted that unlike typical organ transplants with about a 10-20% rejection rate, face transplants have an 80% rejection rate in the first year (Kollar et al., 2018). Early detection of rejection could be vital in helping a transplant recipient save their new face. Although biopsies of the transplanted tissue could provide such early detection, the side effects of scarring, infection or even initiating rejection are too risky.

Instead, the researchers decided to test proteomics’ potential to deliver a “liquid biopsy” blood test for early signs of rejection (Kollar et al., 2018). Using six patients (a small number when considered in its own right, but a huge fraction of actual face transplant recipients), the researchers harnessed SomaLogic® technology to look at serum samples that had been collected at different times, including before and after a tissue rejection was detected. In their analysis, the researchers found changes in five blood proteins that tracked well with severe rejection versus nonsevere or no rejection: Specifically, the proteins matrix metalloproteinase 3 (MMP3), aminoacylase-1 (ACY1), interleukin-1 receptor type 2 (IL1R2), kallistatin (SERPINA4) and carboxypeptidase B2 (CPB2). The identification of the proteins also offered a glimpse into the molecular processes of the body’s rejection of the new face.

From the five proteins identified, the researchers homed in on MMP3, which was the most elevated in severe rejection events. They surmised that the elevated levels of that protein may be indicative of continuous damage and repair of the tissue, which might alter the tissue’s configuration (Kollar et al., 2018). More work, however, is necessary to confirm this idea.

Although many ideas from this work still require validation, one cannot deny the potential impact of the work. From a small study that represents a significant proportion of the number of face transplant recipients, proteomics may have begun to uncover a means to provide early warning of a severe rejection event, free of subjective observations. The early detection could result in earlier intervention, which could potentially help the patients save both their face and their ability to navigate the social world without additional duress.

 

References

Kollar, B., Shubin, A., Borges, T. J., Tasigiorgos, S., Win, T. S., Lian, C. G., . . . Riella, L. V. (2018). Increased levels of circulating MMP3 correlate with severe rejection in face transplantation. Sci Rep, 8(1), 14915. doi:10.1038/s41598-018-33272-7

Rifkin, W. J., Kantar, R. S., Ali-Khan, S., Plana, N. M., Diaz-Siso, J. R., Tsakiris, M., & Rodriguez, E. D. (2018). Facial Disfigurement and Identity: A Review of the Literature and Implications for Facial Transplantation. AMA J Ethics, 20(4), 309-323. doi:10.1001/journalofethics.2018.20.4.peer1-1804

 

I Can Hear You Now: Listening to Our Proteins to Improve Our Health

I Can Hear You Now: Listening to Our Proteins to Improve Our Health

We easily recall many of our first experiences as they often signal important milestones in our lives. History duly records the first time of many things, such as the first steps on the moon, the first phone call ever made, the iconic story of the first cell phone call, etc. We may be witnessing another important “first.”

Recently, we talked about how our blood is awash with information about what’s happening in our bodies, and how that information might be tapped to glean medical insights. We cautioned that care must be exercised when determining which messages are important so as to avoid missed diagnoses or undergoing unnecessary and invasive treatments. Procedures for extracting medical insights from blood need to be thoroughly vetted in real people to determine the validity of the test in a clinical setting.

We are pleased to announce that the first significant use of our “protein-listening” SOMAscan® platform in a clinical setting has begun recruiting! In a recent press release, our UK collaborators proudly announced that the Leeds Centre for Personalised Medicine and Health enrolled the first person for a study involving 1000 patients. This study will assess how SomaLogic’s proteomic insights can guide a person to adopt lifestyle changes to ward off the onset of type 2 diabetes. Our Chief Medical officer, Steve Williams, MD, noted that this is the “first time in history” that a test involving 5,000 proteins will be used in preventative treatment.

We are excited to see the outcomes from this first clinical application of the SOMAscan platform insights. It could be the emphatic validation that proteomics uniquely provides the right information to identify the right treatment for the right patient at the right time. A true first for human health around the world, and one to remember.

 

Using Proteomics to Realize the Benefits of Burning Off Those Holiday Meals

Using Proteomics to Realize the Benefits of Burning Off Those Holiday Meals

Am I loath to admit it? No. I proudly admit that I joined the ranks of the many people who overate during the holidays. What I do loathe is dusting off that VHS tape to start doing aerobic exercises that promise to turn my various expanded body parts into steel. Though, I have always been told that it is important to at least try. But is it?

While we can easily observe what happens to the exterior of bodies hooked on exercise, what happens on the inside at the molecular level? A team of researchers from the University of Colorado, Boulder have answered that question by measuring protein differences in a cohort of healthy people, both young and old, who either exercised regularly or lived sedentary lifestyles (Santos-Parker, Santos-Parker, McQueen, Martens, & Seals, 2018).

What did they find? When comparing the blood of active and sedentary people, the researchers found that exercise changed the levels of circulating proteins that were involved in stress response, inflammation, immune system and cell death (apoptosis). Some of these changes correlated with measurements typically used to gauge one’s healthspan (how long you stay in good health), such as blood pressure, insulin resistance, etc. The team also corroborated previous findings of exercise-induced alterations in proteins involved in neural development, blood vessel formation, glucose metabolism, muscle enlargement, etc.— processes known to mediate the physical benefits of regular exercise.

Even more interesting for those of us of a certain age, the researchers found that exercise could act as a potential fountain of youth for some processes, such as inflammation and cell stress response. Several proteins whose levels changed with age were partially returned to levels comparable with young people when regular exercise entered into the picture.

The researchers noted that although the work is very encouraging, the findings are still preliminary and require further validation. Nevertheless, the work paves the way for a potentially brighter future for anyone affected by aging – which is, well, everyone. Proteomics may have just provided us with proof that we can slow or reverse processes associated with age-related conditions (Haigis & Yankner, 2010; Sanada et al., 2018). I don’t know about you, but I certainly feel more inclined to start exercising. Where is that VHS tape? It’s time for me to work on building some steel.

 

References

Haigis, M. C., & Yankner, B. A. (2010). The aging stress response. Mol Cell, 40(2), 333-344. doi:10.1016/j.molcel.2010.10.002

Sanada, F., Taniyama, Y., Muratsu, J., Otsu, R., Shimizu, H., Rakugi, H., & Morishita, R. (2018). Source of Chronic Inflammation in Aging. Front Cardiovasc Med, 5, 12. doi:10.3389/fcvm.2018.00012

Santos-Parker, J. R., Santos-Parker, K. S., McQueen, M. B., Martens, C. R., & Seals, D. R. (2018). Habitual Aerobic Exercise and Circulating Proteomic Patterns in Healthy Adults: Relation to Indicators of Healthspan. J Appl Physiol (1985). doi:10.1152/japplphysiol.00458.2018