Author: Staff Page 2 of 3

Author: Emily Cartwright

Editor: Hongyan Hao

As sequencing costs drop and more companies develop genomic testing for everything from predicting hair color to the risk of disease susceptibility, the public has access to a wealth of personalized health information. At the same time, companies are faced with the decision of how much information to release to the public, only some of which is regulated. The Food and Drug Administration (FDA) has policies on what kinds of information that companies such as 23andMe and Ancestry.com can release to the public, but there are many enterprises that are not clinically certified and utilize genomic data to conduct health studies (1). How to regulate and disseminate findings from these companies, especially smaller scale studies that may not be clinically certified, is an unresolved issue.

Many of the current FDA regulations for companies like 23andMe are disease specific. Regulations released in 2017 allowed 23andMe to report on variants associated with 10 diseases or conditions (2) and in 2018, allowed the release of information on three BRCA1/BRCA2 variants to consumers who submitted for genetic testing (3). These specific BRCA1/2 variants are known to be associated with an increased risk of developing cancer but there are over 1,000 identified BRCA mutations (3). While these regulations limit the amount of information that consumers are provided, they also circumvent the current issue of how to relay health information to patients in a truthful and informative way; where it is made clear that the results of genetic testing indicate the known risk of developing a certain condition.

It is crucial that companies emphasize that not having a genetic marker associated with a disease or condition does not mean that the individual will not develop the condition. Current regulations from the FDA seek to limit what information can be released to the public but do not address how large companies can best convey health information to consumers. There are also gaps in the ability of agencies like the FDA to regulate all health information gleaned from genomic data, as many small companies do not fall under their regulatory jurisdiction (1).

Recently, the National Academies of Sciences, Engineering, and Medicine (NASEM) released a report (4) encouraging researchers to relate findings from biological data analysis back to people whose samples were used in the studies. The report is intended to increase the flow of information from scientists to the public, but a central issue still involves the question of how to convey information in a way that is both meaningful and accurate, in terms of whether or not a finding has medical significance. 

Genetic variants may indicate risk of disease susceptibility, but this is not necessarily causal and relaying such information to the public can be tricky (1). Researchers are also faced with an increased cost of funding for these studies because determining how to relay information to the public and executing this can result in additional expense (1). The NASEM recommended that researchers should plan out what information they will release from their studies prior to starting them, which may also help the researchers to plan out the added cost of relaying this information (1,4).

The flow of information from researchers to consumers is important but the fact that many studies are carried out by third parties also lies at the forefront of this issue. Companies that do not do the initial genomic sequencing and that may not have the clinical or scientific background to make the diagnoses they relay to consumers may give misinformation (1). The New York Times reported on a case where a doctor had sent his genomic data to a third party, Promethease, and was told that he had a variant known to be associated with Lynch syndrome, a disease that predisposes individuals to cancer early in life (5). The variant was associated with the disease but was not known to cause it, and more importantly, after sending out for genetic testing at a medical diagnostic firm, the doctor received results confirming that he did not actually have the mutation (5). The discrepancy in results brings up the issue of who should be allowed to handle genomic data and how should companies that do not fall under the umbrella of FDA regulations be treated (1). Right now, there may not be a good way to handle third party testing centers that have not been clinically certified, but consumers should be aware of the potential misinformation in results from these companies.

While there are still grey areas concerning the regulation of findings from studies that utilize genomic information, there is an effort to move towards defining what should be released and how. As researchers move towards utilizing this type of data for health and genetic studies, organizations such as NASEM are becoming more critical to help define what and how this information is treated and disseminated. There are many third-party companies that will not fall under guidelines set out by the NASEM but there is still a need to regulate how and what these companies can do with genomic data as well as how their information is released to the public (1). This can come from both sides, in conveying more accurate and meaningful data to consumers and in being more direct about the difference between association and causality in the relationship of variants to disease or condition.

Works Cited:

1. Couzin-Frankel, J. (2018). If you give your DNA and tissues to science, should you get a peek at what they might contain? Science (New York, N.Y.). http://doi.org/10.1126/science.aau7323
2. Administration, U. F. A. D. (2017). FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions.
3. Administration, U. F. A. D. (2017). FDA authorizes, with special controls, direct-to-consumer test that reports three mutations in the BRCA breast cancer genes.
4. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Health Sciences Policy, Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Downey, A. S., Busta, E. R., et al. (2018). Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. http://doi.org/10.17226/25094
5. Kolata, G. (2018, July 2). The Online Gene Test Finds a Dangerous Mutation. It May Well Be Wrong. The New York Times. Retreived from https://www.nytimes.com/2018/07/02/health/gene-testing-disease-nyt.html

Additional Links:

Spit is a podcast put out by 23andMe and iHeartRadio that features celebrity dialogue, highlighting some of the social issues surrounding genomic data.

On privacy issues surrounding genomic data: https://www.theverge.com/2018/8/1/17638680/genetic-data-privacy-consumer-rights-guidelines-23andme-ancestry

And in the news: https://www.nytimes.com/2018/10/18/opinion/sunday/dna-elizabeth-warren.html

More on the role of NASEM in regulating the release of information from genomic studies: https://www.biospace.com/article/national-academies-report-provide-patients-with-clinical-study-results/

Author: Anna Feitzinger

Editors: Hongyan Hao, Sharon Lee, Keith Fraga

At first glance, science and art may appear to be two areas of human activity that could not be more distantly related. I’d like to dismantle this idea of scientists and artists and explore the qualities shared by both. Neon color tube racks and primary-colored pipette tip boxes are some of the basics that are scattered about the biologist’s benchtop. Biologists often visualize the microscopic world using dyes or fluorescent molecules and lasers of various wavelengths of light. The result is an image (or video) of colorful molecules whose arrangement depends on the particular cellular landscape and whose interpretation is up to the scientist. In fact, the first image that surfaces when searching “immunostaining” resembles that of a Paul Jackson Pollock painting (Figure 1).

Figure 1.  Left: Immunostained section of brain tumor in Wikipedia, The Free Encyclopedia. Right: Number 1, 1949 by Jackson Pollock. 

The history of science is full of art. Before cameras, scientists had to draw out their discoveries as lens’ became better at high levels of magnification. Inspired by the drawings in Robert Hooke’s Micrographia, the tradesman Antony van Leeuwenhoek learned how to grind lenses so to take up the hobby of microscopy. He made the most powerful lenses of the time and consequently discovered bacteria, protists, sperm cells, blood cells, rotifers and more before his death in 1723. [1] Although he had no formal higher education, he is now considered the Father of Microbiology.

Another unlikely scientist, Santiago Ramón y Cajal, was a rebellious and anti-authoritarian youngster who was said to have been imprisoned at the age of eleven in 1863 for destruction using a homemade cannon [2]. An avid painter, Santiago’s illustrations of brain and neural anatomy have become iconic. Considered the Father of Modern Neuroscience he postulated the neuron theory; the law of the dynamic polarization of the neuron and discovered the axonal growth cone.

Figure 2: A depiction of neurons in the cerebellum by Santiago Ramón y Cajal

Visual artists confined to physical media must discover the nature of their medium. Different techniques require different media and skills. For instance, one must decide the dilution factor of oil paint to linseed oil or acrylic paint to water in order to create a preferred texture and consistency. Screen printers and photographers must learn the properties of the light sensitive emulsions and films with which they work. Musicians become familiar with the sound waves they produce and modulate. Much like scientists mixing reagents in the lab, artists have an array of media used for experimentation.

Scientists and artists both have a need to share their perceptions of the universe which drives dedication, patience and persistence. Both have visions which they spend years perfecting and require creativity for success. Both get feedback from their peers and share their work with the community. Scientists share their work at conferences and artists do so in galleries or on stage. Occasionally, these two worlds collide. Last year marks the twenty year anniversary of the “Worm Art Show” which was started in 1997 by Ahna Skop at the International C. elegans conference. Works presented at the very first show included the C. elegans genome sandblasted onto a piece of driftwood and a wooden construction of the C.elegans vulva [3]. The American Society of Microbiology now hosts an annual Agar Art competition. This years first place piece, “The battle of winter and spring” features a stunning portrait of two contrasting figures made using colored microbes resistant to different antibiotics on a plate of agar.

Artists and scientists share a common thread historically, and each rely on one another in the modern world. Some recent collaborations include the turning of data into sound, called sonification. Mark Ballorad of Pennsylvania State University in State College has received two $50,000 grants for a project aiding marine biologists in translating data from the deep ocean into sound. Being able to listen to large data sets allows for an entirely different perspective that may not be captured by more conventional visualization methods. A recent publication by a music professor and chemical biologist explore how turning protein sequence and structural information into melodies can facilitate analysis.

Here at UC Davis the Department of Design hosts the LASER Series: conversations in art and science. Each LASER event has four presentations from four different disciplines as unrelated as possible. These talks are meant to facilitate interdisciplinary conversations between artists, scientists and generalists. The seminar is part of an international speaker series, all which are documented and accessible online. Another Art/Science initiative on campus is the Art/Science Fusion program which aims to bring creative energies from the arts and sciences to foster innovation.

[1] Kruif PD (1926) Microbe Hunters. Transactions of the American Microscopical Society 45(3):259.

[2] McMenemey, W. H., M.D. (1952). Section of Pathology (Vol. 46). Proceedings of the Royal Society of Medicine.

For updated information on the LASER series at UCD: https://www.facebook.com/laser.ucd

Additional articles on this topic:

https://www.forbes.com/sites/quora/2016/03/16/why-art-and-science-are-more-closely-related-than-you-think/

https://www.ebsco.com/blog/article/the-steamy-relationship-between-art-and-science

https://cosmosmagazine.com/society/when-arts-and-science-collide

Author: Hongyan Hao

Editors: Anna Feitzinger | Emily Cartwright, Keith Fraga, Jessica Huang, Sharon Lee, Yulong Liu, Linda Ma

Long distance cargo transport in neurons is facilitated by microtubule motors kinesin and dynein. In vivo, microtubules are crowded environments covered by different kinds of microtubule associated proteins (MAPs). How do motors react when they encounter MAPs? A recent work entitled ‘competition between microtubule-associated proteins directs motor transport’ published in Nature Communications by  Ph.D. student Brigette Monroy in the Biochemistry, Molecular, Cellular, Developmental Biology (BMCDB) program explored how different MAPs directs motor movement on the microtubules.

My ability to write this article depends on my nervous system formed by numerous cells called neurons. Neurons communicate with each other through a long cable-like projection termed an axon, and branched cellular extensions called dendrites. The axons of our motor neurons can extend all the way from the spinal cord to our toes, which can be 1 meter in length. Thus, neurons are faced with the significant challenge of transporting proteins, vesicles and organelles over long distances to maintain cell polarity and the connection between neurons.

Hollow tubes called microtubules (MTs) are the highways for effective intracellular transport from the axon or dendrite to the cell body.  Motor proteins kinesin and dynein are the trucks traveling along the MTs. Polarized with two distinct ends, i.e. a plus end and a minus end, MTs are one-way-only tracks for both motors. Kinesin-1 is plus end directed while dynein moves towards the minus end of MTs. Thus, the organization of the MT is essential for directing cargos to their correct destination.

Microtubule (MT) plus-end motor kinesin-1 and kinesin-3 are inhibited by tau patches, while tau has little effect on the MT minus-end motor dynein. MAP7 outcompetes tau and specifically enhances kinesin-1 movement. Similar to tau, MAP7 inhibits kinesin-3 but allows for the dynein movement.

In axons, MTs are highly organized into bundles with plus ends directed out towards the cell periphery, and minus ends oriented inward towards the cell center. In contrast, MT orientation is mixed in dendrites (1). In vivo, MT organization and dynamics are highly regulated by microtubule associated proteins (MAPs). For example, the MAP tau binds to the MT lattice and stabilizes axon MTs. When detached from the MT, tau proteins form aggregates, which is one of the hallmarks of Alzheimer’s disease (2). Another MAP, MAP7, also known as ensconsin or EMAP-115, binds to MTs at axon branch sites to positively regulate branch formation (3). As the MTs are decorated by different kinds of MAPs in axons and dendrites, how do the motors dynein and kinesin behave when they hit MAPs?

MAPs are not just rocks on the road that block motors. In fact, the two motors will respond differently depending on which MAP they encounter. For instance, previous studies have shown that kinesin-1 motors will stop and fall off when they encounter tau, while tau has little effect on dynein (4, 5). In contrast, MAP7 enhances kinesin-1 movement (6, 7). How do these different motors and MAPs coordinate with each other to achieve effective cargo transport in axons and dendrites?

A recent publication by BMCDB student Brigette Monroy and her colleagues from Kassandra Ori-McKenny’s lab at UC Davis explores how motor movement might be regulated by different MAPs coating the MTs (8). Consistent with previous reports, Monroy et al. found that tau is restricted to axons, but MAP7 was localized to both axons and dendrites in the Drosophila peripheral nervous system and tissue cultured mouse neurons. Using Total Internal Reflection Fluorescence (TIRF) microscopy, which allows for visualization of molecules on a single stabilized MT in vitro, the authors found that MAP7 strongly excluded tau from the MTs. Although bound to MTs more rapidly than MAP7, tau is displaced by MAP7 over time.  This is most likely due to MAP7’s higher MT-binding affinity and longer dwell time on the MT lattice since purified MAP7 and tau do not bind to each other (8).

It is striking that MAP7 kicks tau off the MTs, but what are the physiological functions of MAP7/tau competition? Overexpression of MAP7 in Drosophila larval dendritic arborization (DA) neurons caused increased branch number while tau overexpression led to a decreased branch number. Overexpression of both MAP7 and tau led to more branches in DA neurons, consistent with the observation that MAP7 outcompetes tau (8).

One possible mechanism is that MAP7 and tau affect DA neuron branching by regulating the intracellular transport of the Golgi outposts. Golgi outposts are important for branch formation by nucleating MTs at branch sites (3, 9). The increased branching observed with MAP7 overexpression may be due to increased kinesin-1 mediated cargo transportation since Golgi were found to be enriched in the plus ends of MTs in DA neurons.

In vivo studies have revealed positive regulation of kinesin-1 by MAP7, but the mechanism has been unclear (7). Using in vitro single molecule motility assays, where the movement of a single fluorescently labeled motor protein on the MT is observed under TIRF microscopy, Monroy et al. found that both human and Drosophila MAP7 directly affect kinesin-1 by enhancing the motor landing on the MT. This may be due to 34 conserved amino acids in MAP7 which may facilitate kinesin-1 recruitment through a weak, ionic interaction with kinesin-1. Kinesin-1 motors stop and fall off the MTs when they encounter patches of tau. Would the presence of MAP7 overcome tau’s inhibition on kinesin-1? The answer is yes. MAP7 can not only replace tau on the MT and recruit kinesin-1 onto the MT, but also restores the ATPase activity of kinesin-1 inhibited by tau.

Tau has little effect on dynein motors. What about MAP7? Interestingly, just like tau, MAP7 barely affects the mobility of the dynein active complex in vitro. So, does MAP7 only affect plus end MT motors? Kinesin-3 family motors are also plus end directional. In contrast to kinesin-1, MAP7 inhibits kinesin-3’s landing on the MT as well as its mobility. However, tau inhibits kinesin-3 in a similar way as kinesin-1.
Cells have very complex environments and it is challenging for in vivo studies to provide clear and detailed mechanisms of how proteins work with one another. On the other hand, in vitro results can be difficult to interpret because simplified systems introduce biases not present in cells. In this paper, the Ori-McKenny lab illustrates how powerful it is to combine in vitro and in vivo studies to investigate the mechanism of cellular processes.

MTs are essential to maintain the shape, polarity and intercellular transport in our neurons. The findings suggest that MAPs on the MTs coordinate with each other and that MT motors can interpret MAPs, which allows for the regulation of cargo transport. Monroy’s story only discussed MAP7 and tau, but MTs are also occupied by other MAPs. Also, MTs can be post-translationally regulated to favor or inhibit motor mobility. I am grateful that our neurons have a system to coordinate cargo transport, which makes up a powerful neural system that enables me to ponder the relationship between different MAPs, motors and how they are doing their jobs together on the MTs! I am excited to see what Monroy and Ori-McKenney come up with next! A more complex map about motors and MAPs is yet to be revealed!

Now, after sitting here for a while, I have decided to walk out to get a cup of iced tea. I suppose that the kinesin and dynein motors made their ways to the right destination and the long motor neuron axons delivered the message to my toes, since I made it to the long line and am enjoying it now.

References:
1.         Burton PR (1988) Dendrites of mitral cell neurons contain microtubules of opposite polarity. Brain Res 473(1):107-115.
2.         Ballatore C, Lee VM, & Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9):663-672.
3.         Tymanskyj SR, Yang B, Falnikar A, Lepore AC, & Ma L (2017) MAP7 Regulates Axon Collateral Branch Development in Dorsal Root Ganglion Neurons. J Neurosci 37(6):1648-1661.
4.         Ebneth A, et al. (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: Implications for Alzheimer’s disease. Journal of Cell Biology 143(3):777-794.
5.         Dixit R, Ross JL, Goldman YE, & Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319(5866):1086-1089.
6.         Barlan K, Lu W, & Gelfand VI (2013) The Microtubule-Binding Protein Ensconsin Is an Essential Cofactor of Kinesin-1. Current Biology 23(4):317-322.
7.         Metzger T, et al. (2012) MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function. Nature 484(7392):120-+.
8.         Monroy BY, et al. (2018) Competition between microtubule-associated proteins directs motor transport. Nat Commun 9.
9.         Ori-McKenney KM, Jan LY, & Jan YN (2012) Golgi Outposts Shape Dendrite Morphology by Functioning as Sites of Acentrosomal Microtubule Nucleation in Neurons. Neuron 76(5):921-930.