Crowdsourcing the stock market

New market tools are emerging that could be much better (real-time and objective) indicators of performance than the traditional methods of speculation-driven stock market price, quarterly reporting, and financial statements.

These tech tools are a nice response to the perceived social economic malaise of the times, and could help to realize some of the new thinking promulgated by both theorists and activists that markets are more of a Darwinian game of the fittest rather than an invisible hand meeting favorably for all parties.

The new market tools - real-time performance indicators:

• Prediction markets (SimExchange, Hollywood Stock Exchange, Intrade) for unit sales data
  
• Real-time purchasing feeds (Blippy, Google Wallet, social shopping sites) for the aggregation of real-time purchase data
• Social media check-ins (FourSquare, Facebook, etc.) for revenue prediction
• Forum badging and site gamification (Badgeville) for measuring the digital economics of brand sentiment

Programmable RNA and other recent advances in synthetic biology

There were 50-100 attendees at the Cell Press-sponsored Synthetic Biology conference at the University of California, San Francisco held on December 14, 2011. There was the usual acknowledgment of the field’s status (early-stage), potential impact (considerable), and articulation of what is needed (easy-to-use tools, reliable at-scale design and manufacturing processes, and standardized interoperable parts libraries) that has been typical at group gatherings (e.g.; SB 5.0) for the last few years. Also the point about a better marketing approach to attract scientists and public support to the field, something more enticing than the admittedly deadpan…

We pipette colorless liquids from one tube to another … we’re trying to cure cancer and change the world.

What was different was the degree of sophistication in the approaches, the easy multi-disciplinarity that researchers are bringing to the field, a more comprehensive understanding of the constituent materials (for example, the 5’ DNA does a lot of things: degradation, elongation, binding, etc. in a dynamic system where different processes come online to change resource use per osmolarity, temperature, etc.), and the contemplation of process portability across model organisms, for example from yeast to mammalian cells. The conference structure focused on the overall status and issues of the industry in a panel with leading scientists, and had talks regarding foundational technologies and applications.

Key points made by synthetic biology visionary Drew Endy (Stanford)

• Biology is the best manufacturing partner we’ll find, it has taken over the earth; biology is interesting as both a type of inquiry (we don’t understand everything yet) and as a building material
• Design experts (e.g.; from RSID, the New School, etc.) should be brought into biological design
• Bio-manufacturing is big, but storing data in cells could be bigger
• Metrology advances are needed, in units, reference standards, etc.; for example when shipping a gene expression module to colleagues in Shenzhen, what units should be employed?
• 4-D space-time programming languages is an important new area, only six people worldwide are thinking about this so far
• We need to do regenerative medicine without scaffolds, we know biological cells can differentiate into 3-D, how can we engineer this to happen?
• Synthetic biology needs to expand beyond the few workhorse chemicals used all the time like theophylline and tetracycline
• An important application area is drug design since small molecules, the main current paradigm used in drug development, are limited by their surface area, where they can travel to in the body, and other internal properties

Key conference themes

RNA as a programmable material
Programmable materials are an important input to synthetic biology as they may allow ongoing control over the dynamic processes of living cells. RNA is exemplar as a programmable substrate since it can be used to sense the presence of small molecules in cells and control gene expression by influencing which proteins are made and many other cellular activities [1]. In the keynote talk, Gerald Joyce (Scripps) discussed the specifics of exploiting RNA with a technique analogous to PCR (polymerase chain reaction), where an exponential number of copies of DNA are made to trigger desired cellular behaviors. In this case, an exponential number of copies of certain ligands (building-block molecules that bind with other molecules to trigger reactions in cells) are made that a certain enzyme-making RNA binds to for carrying out a desired cellular function [2].

Not only can RNA be used on a unitary basis to direct cellular actions, it can also be used as a component in constructing gene networks that serve as sophisticated molecular control devices like switches and circuits. Christina Smolke (Stanford) presented research using RNA to build synthetic controllers, for example a ribozyme-based device that can be used to detect metabolites non-invasively, a ribosome binding site-based device that can degrade harmful chemicals into neutral products, and a splicing-based device that can be used to target cell death [3]. A potential application was discussed using a synthetic RNA device to regulate cell signaling and T-cell proliferation in mammalian cells [4]. Alan Arkin (UC Berkeley and LBNL) suggested desirable ways to increase the complexity of synthetically generated devices, for example, assembling complexity from the constituent properties of the materials that is modular or context-free in deployment, and by having diverse RNA control elements on a single transcript [5]. This could also make devices more replicable.

Manipulating organelles
After the theme of RNA as a programmable material and synthetic genetic network regulatory element, another de facto theme was the capability to manipulate organelles.

David Savage (UC Berkeley) presented work regarding carboxysomes (protein-enclosed bacterial organelles). Synthetic organelles could be constructed that would be useful for a variety of cellular activities, including improving on current biological processes like RuBisCO leakage (an enzyme involved in the first major step of carbon fixation). Synthetic organelles could be developed based on previous work characterizing carboxysomes with shell and cargo fluorescent tagging [6], and recent work improving the stability and well-formedness of shells through shell-protein modification, particularly by adding a novel protein, CsoS1D, discovered by Cheryl Kerfeld’s lab (UC Berkeley and LBNL) [7,8].

Wallace Marshall (UCSF) discussed the importance of understanding and controlling organelle size, shape, and composition, the trade-offs between lipid and starch storage and controlled metabolism, for example. Tuning flagellar length could be important in the understanding and remedy of ciliary diseases [9], and experimental research suggested in one case that the quantity of LF4 (long flagella) protein being injected could be the key fulcrum of the control system. Organelle-tuning could have a broad range of useful applications, for example tuning up and down the ability of vacuoles to tolerate toxic compounds.

Applying synthetic biology to drug design
Michelle Chang (UC Berkeley) pointed out how the toxicity of fluorine makes it useful in drugs, and perhaps synthetic biology techniques could improve its effectiveness. A naturally-occurring fluorine-specific enzyme (FIK) was examined that demonstrated dramatic improvement in recognizing molecules [10]. Leor Weinberger (Gladstone Institute and UCSF) discussed synthetic viral circuits called therapeutic interfering particles (TIPs) that have been shown to reduce HIV/AIDS infection rates. The TIPs replicate conditionally in the presence of the pathogen and spread between individuals [11].

Developing foundational technologies
Hana El-Samad (UCSF) discussed the benefits of using hybrid biological and computer-based systems, where software algorithms were used to control a gene expression circuit’s behavior in real-time through a light-responsive module [12].

John Dueber (UC Berkeley) discussed the benefits of controlling the volume of enzymes expressed in cells, optimizing flux through cells. A desirable tool for this is combinatorial libraries to manage expression in multi-gene pathways. Further, when there are flux limitations in the pathway that cannot be managed with gene expression, there has been some interesting work building synthetic scaffolds to co-locate pathway enzymes around the areas of interest [13].

Nathan Hillson (LBNL) presented ways to automate and speed up the engineering cycle (design-build-test) with a component repository, selected components, and assembled components. Software design automation for assembly tools were discussed such as the JBEI-ICE repository platform and the GLAMM design tool.


References

1. Liu CC, Arkin AP. The case for RNA. Science. 2010 Nov 26;330(6008):1185-6.
2. Lam BJ, Joyce GF. An isothermal system that couples ligand-dependent catalysis to ligand-independent exponential amplification. J Am Chem Soc. 2011 Mar 9;133(9):3191-7.
3. Liang JC, Bloom RJ, Smolke CD. Engineering biological systems with synthetic RNA molecules. Mol Cell. 2011 Sep 16;43(6):915-26.
4. Chen YY, Jensen MC, Smolke CD. Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems. Proc Natl Acad Sci U S A. 2010 May 11;107(19):8531-6.
5. Lucks JB, Qi L, Mutalik VK, Wang D, Arkin AP. Versatile RNA-sensing transcriptional regulators for engineering genetic networks. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8617-22.
6. Savage DF, Afonso B, Chen AH, Silver PA. Spatially ordered dynamics of the bacterial carbon fixation machinery. Science. 2010 Mar 5;327(5970):1258-61.
7. Roberts EW, Cai F, Kerfeld CA, Cannon GC, Heinhorst S. Isolation and Characterization of the Prochlorococcus Carboxysome Reveals the Presence of the Novel Shell Protein CsoS1D. J Bacteriol. 2011 Dec 9.
8. Klein MG, Zwart P, Bagby SC, Cai F, Chisholm SW, Heinhorst S, Cannon GC, Kerfeld CA. Identification and structural analysis of a novel carboxysome shell protein with implications for metabolite transport. J Mol Biol. 2009 Sep 18;392(2):319-33.
9. Wemmer KA, Marshall WF. Flagellar length control in chlamydomonas--paradigm for organelle size regulation. Int Rev Cytol. 2007;260:175-212.
10. Weeks AM, Coyle SM, Jinek M, Doudna JA, Chang MC. Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity. Biochemistry. 2010 Nov 2;49(43):9269-79.
11. Metzger VT, Lloyd-Smith JO, Weinberger LS. Autonomous targeting of infectious superspreaders using engineered transmissible therapies. PLoS Comput Biol. 2011 Mar;7(3):e1002015.
12. Milias-Argeitis A, Summers S, Stewart-Ornstein J, Zuleta I, Pincus D, El-Samad H, Khammash M, Lygeros J. In silico feedback for in vivo regulation of a gene expression circuit. Nat Biotechnol. 2011 Nov 6;29(12):1114-6.
13. Whitaker WR, Dueber JE. Metabolic pathway flux enhancement by synthetic protein scaffolding. Methods Enzymol. 2011;497:447-68.

Empathy-building 101: the top 10 list

Some important social intelligence skills are empathy, compassion, and a positive mental outlook. These skills can be taught as any other skills such as leadership and goal-setting. Some of the important aspects of developing empathy are self-awareness, self-compassion, active listening, and the ability to experience or identify with the thoughts and emotions of others.

One way to deliver social intelligence-building experiences is on the mobile platform. A virtual coach ('Siri 2.0') can send you randomly-timed messages like the examples below. If you are interested, sign up now for the beta launch the DIYgenomics Social Intelligence Mobile app by messaging our personal virtual coaches led by Marbet Grant 650-209-0872 or marbetgrant AT gmail.com.

1. What is one of your best qualities? Think about how you know you have this quality. Who else has this quality? Where are useful places in your life that you might use this quality?
2. Think of three goals you plan to accomplish today or tomorrow and write them down
3. When you really stop to think about it, what is really great about your life right now?
4. Where are you today? How are you feeling in your body right now?
5. What do you feel grateful for right now?
6. What’s one of your biggest flaws that a lot of other people might have too?
7. Think of a recent situation where you noticed the emotion experienced by someone else and get a sense what that must feel like
8. Take a moment, drop inside and get a sense of how you are felling right now, describe this with some emotion words
9. Think of a recent situation with someone else that didn’t go as well as you wanted. Put yourself in the other person’s position and identify what positive intent they may have had for the way they behaved
10. Ask yourself what you really want out of this current work project (or job or relationship). Say this back to yourself, ‘so what you really want in this [project, job, relationship] is _________’ and see what you notice

Anxious uncanniness drives technological phase change

There is an interesting link between philosophy, technology innovation, and complexity theory. A claim has arisen that people may be feeling unsettled, that they no longer belong to certain normative groups like ‘Americans’ or ‘doctors.’ One reason could be the fast pace of technology innovation and adoption which has been creating a pervasive, accelerating, and possibly irreversible culture of biotechnicity. Paradoxically, technology innovation may also be the resolution.

This feeling of being unsettled is that of experiencing an anxious uncanniness of what it means to be a doctor, a Christian, a New Yorker, or whatever. This has long been identified by philosophers (e.g.; Plato, Socrates, Kierkegaard, etc., and more recently Jonathan Lear) as (a lesser-known definition of) irony; when individuals experience a sense of dissumlation (dissimulation).

A further claim is not that anxious uncanniness is harmful or undesirable, but rather that ironic uncanny experiences should be cultivated as the only way out, a key means of growth. Growing by pushing out of one’s comfort zone is parallel to dynamics in the cycles of technology innovation and complexity theory. In technology innovation, the chaotic foment at the end of a paradigm (like the vacuum tube or perhaps oil) forces innovation into a new paradigm. In complex systems, after symmetry-breaking and the development of entropy, adding energy helps to rebalance systems to attain the next node of progress.

Big data quantitative analysis toolkit

Just like data bytes may become much more richly modulated with attributes (an extension of data provenance; modulating data bytes with additional inspectable elements such as create/review/launch time stamps, and owner, quality, freshness, and controversy properties, etc.), so too may quantitative data sets.

There should be a ‘2.0 format’ standardized toolkit for quantitative data analysis that includes the top ten techniques often used to analyze data sets. These tools should be user-friendly, ideally as a widget overlay to websites, or otherwise easily accessible and usable by non-quant laypersons.

Suggested techniques for inclusion in the top ten most-useful data analysis tools:

1. Fourier transforms
2. Markov state models
3. Entropy analysis
4. Distribution analysis (e.g.; power law, Gaussian, etc.)
5. Progression analysis (e.g.; linear, geometric, exponential, discontinuous)
6. Qualitative math
7. Network node/group theory/graphing theory analysis
8. Complexity, chaos, turbulence, and perturbation modeling
   

It could become standard that these kinds of techniques are automatically run and displayed on large data sets.

Mental performance optimization

Much time is devoted to maintaining physical health through exercise but almost nothing is done to maintain mental health. The positive psychology movement, happiness research, persuasive behavioral change techniques, calming technologies, and books such as the Neuro Revolution have helped to destigmatize mental health as a focal point for improvement. The next big wave in mental health and performance optimization could come from mobile phone apps. The continuous intimate experience with these inseparable human appendages makes them perfect tools for managing mental health.

The first generation of mental performance mobile apps has been mainly for data collection. Subsequent generations could extend into targeted interventional strategies and ongoing performance management. NLP (neuro-linguistic programming) techniques could be used to shift attention to productive areas, shape goals and action steps, reframe unpleasant experiences, identify and bring out internal resources, and otherwise facilitate better feelings and experiences.

Citizen science health tools

The number of citizen science health and biology projects has been growing in the last few years due to a confluence of factors. Some of these include the plummeting cost of DNA sequencing, the availability of bioinformatics and other web-based data interpretation tools, the possibility of ordering direct-to-consumer blood tests, and having community DIYbio labs for experimentation, education, and support. DIYgenomics has developed a number of boilerplate tools to help in the design and conduct of citizen science health projects:

Study design and organization

• Study design template

Legal/ethics

• Sample informed consent form

Finance

• Study budget template

Recruitment and marketing

• Study flyers: multiple studies, aging study, vitamin deficiency study
• Conference poster
• Participant recruiting plan (per Genomera)
  

Quantization trends of the future: crowdsourcing and geolocation

Two conferences held in San Francisco last week underline key future trends, the crowdsourcing of work (and maybe everything), and hyper-local mobile-phone based services such as payments. Thematically, crowdsourcing and mobile services both deal with quantization – the idea of resources being granularized to the smallest unit, and then directed fungibly and automatically to where they are needed and requested, like routing internet data packets. In this case labor units and targeted personalized mobile services can be delivered on a quantized basis. Market principles continue to seep into life with quantization models which typically provide superior value creation and exchange.

Crowdsourcing
CrowdConf2011 (November 1-2, 2011) was bigger and broader than CrowdConf2010. The main focus continued to be on crowdsourced labor, but these models are also emerging in e-government, consumer travel, entertainment, fundraising, and philanthropy (and health, though not included at CrowdConf). Software, professional services (i.e.; graphic design) and R&D have long been staples of crowdsourced labor, and these models are now being extending to almost all areas of the enterprise including sales, social CRM (customer relationship management) and finance, accounting, and administration.

Mobile-phone based services
Mobile is the platform. One billion smartphone users are expected by 2013 and app downloads grew explosively from 300 million in 2009 to five billion in 2010. Arguably, the mobile phone has become an indispensable human augmentation accessory: the loss of a phone is noticed within five minutes, versus the loss of a wallet which takes an hour. The intimate continuous connection individuals have with their mobile phones suggests the platform as a critical delivery mechanism for many important future services such as mental mood performance optimization.

Geo-Loco (November 3, 2011) focused on hyper-local mobile services delivery. The biggest growth area is mobile payment programs where the prevailing methods in use are 2-D barcodes (as used in Starbucks smartphone apps) and NFC (near field communication) chips which send encrypted data over short distances. The development of corporate and brand marketing strategies for mobile services delivery was another big focal area. The poster-child of success of branded smartphone apps, from Starbucks, allows payments, store locating, and checking nutritional information. Ironically, drinks can be configured out of 85,000 possibilities and shared with friends, but not actually ordered!

Job of the near-future: health advisor

The health advisor is analogous to the financial advisor or mortgage broker that arose last decade when it became possible to trade stocks and get mortgage quotes on the internet. This advisor is familiar with the whole ecosystem of services and service providers in a sector whether finances, home buying and selling, or in this case, personalized health management.

The health advisor designs comprehensive wellness plans that integrate multiple health data streams such as family history, personal health history, genomics, and eventually microbiomic, proteomic and metabolomic profiles. The health advisor would recommend what type of genomic sequencing to sign up for (for example, 23andMe genotyping or Illumina whole human sequencing) and interpret the results and suggest action items. The health advisor would recommend and administer self-tracking programs and gadgets for diet, nutrition, medication and supplementation, exercise, and sleep management. The health advisor would recommend clinical trials or crowdsourced health studies that might be relevant for individuals to join. The health advisor could be compensated with pre-tax HSA (health savings account) dollars or other tax-advantaged funds.

This is a job category of the near future, as health advisor certification programs and wellness coaches are already arising.

Advances in translational antiaging skin research

There are many exciting innovations in translational anti-aging skin research. Personalized genomics is an important emerging field of science being applied to human biology with applications in skin disease risk assessment, wellness profiling, and product response customization.

Simultaneously, there are promising anti-wrinkle remedies being commercialized such as cellular therapies, topical treatments, retinoid and botox substitutes, and advances in skin manufacturing initially developed by the military for battlefield healing are starting to be applied to the aesthetic dermatology market, for example, dermal substitutes, next-generation skin grafting, and spray-on skin.

Excerpted from Translational antiaging skin research.

Complement proteins: possible predictive biomarker of Alzheimer’s disease

Recent research has uncovered more details about how the brain works. As brains develop, the many initially-formed synapses get pruned. How this occurs is important to understand as synapse pruning also occurs in neurodegenerative disease.

In synapse pruning, many mechanisms are operating together in a systems biology fashion, but one key dynamic is that protein molecules (complement proteins C1q and C3) are tagging weak synapses for elimination. For example, complement protein molecules are massively upregulated in Alzheimer’s disease. The Cq1 genes have been shown to come on very early in the case of glaucoma and are proposed to be a global dynamic of synaptic loss in neurodegenerative disease (e.g.; Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, etc.).

The early and prominent role of complement genes and proteins suggests the possibility of measuring them as a predictive biomarker of neurodegenerative disease.

Steady advance of stem cell therapies

Stem cell research and related therapies (including regenerative medicine and cellular therapies) is an industry with a strong possibility of having a significant near-term impact on worldwide public health. One reason is the industry’s linkage between policy, science, industry, and patient advocacy, as was clear in the attendance and programming at the 7th annual World Stem Cell Summit held in Pasadena CA, October 3-5. Other science-driven fields such as synthetic biology, nanomedicine, and aging might benefit from cultivating such a multi-disciplinary perspective. Stem cell therapies are useful not only in cell-replacement therapies, but also in disease modeling, drug discovery, and drug toxicity screening.

Disease therapeutics and clinical trial focus
Stem cell therapies are currently being applied to over 50 diseases particularly in the areas of heart, lung, neurodegenerative, and eye disease, and cancer and HIV. Dozens of companies are developing therapeutic solutions which are in different stages of clinical use and clinical trials. Some high-profile therapies include Dendreon’s Provenge for prostate cancer, Geron’s first-ever embryonic stem cell trials for spinal cord injury, Fibrocell’s laViv cellular therapy for wrinkles, and well-established commercial skin substitutes (Organogenesis’s Apligraf and Advanced BioHealing’s Dermagraft).

Policy
Stem cell policy issues under consideration include medical tourism, standards for large-scale stem cell manufacturing, and lingering ethical debates over the use of embryonic stem cells.

Science
Contemporary stem cell science advances include a focus on techniques for the direct reprogramming of cells from one lineage to another without having to return to pluripotency as an intermediary step, improved means of generating and measuring induced pluripotent cells, and progress in approaches to neurodegenerative disease, for example establishing causal factors for early-onset Parkinson’s disease, generating neuronal cells and dopaminergic cells, and neural stem cell lumbar implantation clinical trials.

Blood Tests 2.0 advances with dried blood spot testing

Moving into an era of preventive medicine and health self-hacking, blood tests 2.0 is an obvious area for expected innovation, moving whole classes of blood tests from $100+ lab-administered arm draws to fingerstick tests conducted at home. One of the most promising techniques for realizing blood tests 2.0 is dried blood spot (DBS) testing. From a biochemistry perspective, the volume of blood taken in a serum draw is not required for many tests; a few drops would be adequate for many tests. Some exciting recent progress in dried blood spot testing was announced with NanoInk’s protein biomarker detection platform, based on dip pen nanolithography, which was used to identify and quantitate four clinically-relevant cytokines. The technology cannot detect everything, but could possibly be used to identify hundreds of proteins, and pave the way for low-cost home blood marker monitoring.

Home-administered fingerstick tests are already available for several markers, although the cost is not necessarily cheaper and a health care professional may still need to be involved. Blood spots from a fingerstick are placed on filter paper to dry and then sent to a lab for analysis. Tests are available for vitamin D, hormone levels (including estradiol, progesterone, testosterone, and cortisol), cardiometabolic markers (including insulin, high sensitivity C-reactive protein, total, HDL and LDL cholesterol, hemoglobin A1c, and triglycerides) from ZRT Labs. Theoretically, dozens of blood tests could be re-invented as fingerstick tests that are self-administered and interpreted in easy diagnostic readers or mobile-phone attached sensors.

Robotic benefits could accelerate into the service and software industries

An animated discussion about the future of robotics occurred at the September 24, 2011 Boulder Colorado Future Salon. One claim is that the last few decades in robotics might be analogous to the status of the computing industry in the 1950-1970s, growing slowly but surely, and suggesting that the pervasiveness and impact of robotics could start to accelerate. There has been significant progress in agricultural automation and factory automation, and this could spread rapidly to service industries and information technology industries.

On the one hand this is the next logical step in fulfilling the ongoing human dream of using technology to provide more free time. On the other hand, while so far robotics has not had a big negative impact on jobs, a more rapid move to automation in more sectors could result in a more significant displacement of human capital.

Industries of the future
There is a tremendous opportunity to identify the industries of the future and start them. Future industries could be clustered by areas such as sustenance (food, energy, and clean resources), health, productive activity, entertainment, and well-being. One obvious group of future technologies will focus on food, for example, vertical farming and lab-grown meat. Mental well-being and enhancement is virtually untapped, although there is some preliminary activity in applying behavioral change and happiness research, and calming technologies. Some key dynamics that govern human behavior will not be going away in the short-term such as the demand for status-garnering and reputation-building (why gaming has been so successful), so industries providing opportunities for this would be well-pitched.

Newtech: enterprise social networks

Like email, instant messaging, and wikis, the latest newtech spreading into businesses is social networks, essentially serving as a private internal version of Facebook and Twitter. Enterprise social networks are used for a number of purposes, first and foremost, status updates to work teams, but also for real-time messaging with colleagues including document transfer, broadcast announcements, and opinion capture via polls. There are several companies in the enterprise social software sector (Gartner chart). Among the most vibrant are Yammer and Chatter (affiliated with salesforce) each of which has over 100,000 corporate customers in a wide range of industries from finance to entertainment to professional sports; Jive is a third large company in the space. The standard pricing model appears to be freemium-based, free for light-users and $5/seat/month for power users. Enterprise social networks are typically externally-hosted.

Two of the key challenges that come to mind with enterprise social software are: consolidation with other internal communications platforms and data mining. As with enterprise instant messaging, archival and retrieval is important, both at the personal level (for productivity) and organization level (for information systems backup and compliance). There need to be effective ways to consolidate and mine multi-platform internal communications. Formalizing the explosion of casual interaction as it naturally occurs could be abstracted into value-added tools such as a codification of internal knowledge and expertise in the internal wiki for training purposes. It might also be possible to integrate communication flows unobtrusively and automatically into prediction markets or other sentiment analysis algorithms to capture opinion about key upcoming events like product launches and quarterly sales results.

Human augmentation substrate: the microbiome

The human microbiome, comprising 10x human cells, is interesting not only for its significant role in determining health, disease, drug response, and individuality, but also in possibly being a less-invasive human augmentation substrate, for example, bringing nanoscale connectivity and memory processing modules onboard via the microbiome.

New research has identified that only five microbial lineages exist on humans: firmicutes, bacteriodetes, actinobacteria, proteobacteria, and other phyla which is surprising compared to the diversity of microbial phyla on Earth. However, within the lineages, there are many strains and species, for example 1,600-2,000 distal gut species of microbial bacteria in each person, only 7% of which were known previously (paper). Gut bacteria is critical to human functioning, one activity is producing butyrate in colon epithelial cells to maintain energy homeostasis. (paper, article)

The microbiome is a complex adaptive system: resilience and vulnerability
Research extends beyond characterization - an investigation of perturbations to the human microbiome has shown resilience in recovery following a disturbance. However there is vulnerability with persistent perturbation. The human microbiome may not reassume its initial state unless the disturbance is at a frequency that the system has experienced before and for some time. In this case, the system may get stuck in an alternative state or local maximum. (paper).

Time, complexity, entropy, and the multiverse

FQXi, the Foundational Questions Institute, held a multidisciplinary meeting investigating the Nature of Time in Scandinavia August 27 – September 1, 2011 (Figure 1). FQXi promulgates original thinking and research on fundamental questions in physics and cosmology through research grants and essay-writing contests on topics such as “The Nature of Time,” and “Is Reality Digital or Analog?”

Figure 1. Multidisciplinary topics covered at the FQXi Time Conference

Time is familiar in the sense of the three space dimensions and the one time dimension around which human affairs in the physical world are organized. Additionally, each person has a subjective and identifiable relationship to time, even though this may be little more than a convenient construct. In science, time has been developed to the greatest degree in physics and cosmology, and in the philosophy of science. Other fields too are starting to consider time more robustly, including complexity, biology, and computation.

The conference addressed the issue of the arrow of time from many perspectives. While most fundamental laws of nature are time-symmetric, some areas have a time arrow flowing in one direction such as thermodynamics, quantum theory, radiation, and gravity. This can be problematic to explain. A suggested analysis structure involving the trade-offs between complexity and entropy as systems evolve over time served as a useful model for analyzing different aspects of time throughout the meeting.

Inciting Brownian motion at the macro-scale

Entropy is the process of moving from order to disorder, for example one’s desk becoming cluttered after being cleaned. In many cases, lower entropy states are desirable as they connote greater order. Without doing work to decrease entropy, it generally increases at the macro level (the spacetime of objects that humans encounter on a daily basis). Entropy increases and time appears to move only forward.

At the micro scale of atoms, Brownian motion occurs (the constant jiggling of atoms), and creates an important case where the Second Law of Thermodynamics (heat eventually dissipates; systems move from being warm to cold) does not hold. Brownian motion at the micro scale also allows fluctuations in the arrow of time and in entropy, e.g.; time may flow forwards and backwards, and there may be fluctuations towards lower and higher states of entropy. This can be seen not just at the very-very small Planck scale and the atomic scale of statistical mechanics (for example, atoms jiggling in a gas), but also at the level of cells in the body, and in another example, pollen cells suspended just the right way in water.

That Brownian motion can occur at the comparatively larger scale of cells suggests that it may occur, or be induced to occur at even more macro levels too. For example, in complex adaptive systems, an economy has phases of Brownian motion, when rational agents are jiggling constantly to make the invisible hand of supply and demand meet. Perhaps incentive structures including policy may be used to facilitate the persistence of Brownian motion and devolution of entropy in macro-level systems.

A system is a balance: complex systems design

The Inconsistency Robustness symposium held at Stanford August 16-18, 2011 featured discussion of a number of challenges that arise in the design of complex systems, and potential solutions to them. The dialogue ranged from computer science details (for example, message passing in concurrent systems) to systemic assessments (for example, ecological concerns and homeostasis). Researcher attendees applied their varied backgrounds to the discussion.

A universal point in complex systems design is the importance of expecting and incorporating inconsistency and potential points of failure into a system. Flexible robust systems may be dynamical and adaptive within boundaries (Figure 1 - "Complex Dynamical") provided there is some mechanism for identifying and monitoring potential out-of-bounds conditions.

Figure 1. Three patterns of behavior in complex dynamical systems (Source)

Scaling citizen health science and ethical review

Many things are needed to scale citizen science from small cohorts on the order of a few individuals to medium and large-sized cohorts. Building trust in online health communities, motivating sustained engagement from study participants, and lower-cost easier-access blood tests are a few things that are needed.

Legal and ethical issues are also a challenge. Independent ethical review is appropriate but the current IRB (Institutional Review Board) requirement for funding and journal publication is a barrier to crowdsourced study growth. In 23andMe's early studies, there was a definitional debate as to whether their research constituted 'human subjects research,' and whether there was a difference in interacting with subjects in-person versus over the internet.

The U.S. HHS (Health and Human Services) definition of 'humans subjects research' is research that "obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information." (45 CFR 46.102(f)) The strict reading is that any research obtained by 'interacting' with a human subject (e.g.; likely all personalized health collaboration community research) would require an IRB for the funding needed to do it at scale.

Acknowledgement: Thank you to Thomas Pickard for providing background research

Further advance in the integration of organic and inorganic matter

A fundamental research focus in nanotechnology is the deliberate creation of organic-inorganic hybrids such as rotaxanes that have the properties of both organic and inorganic matter. These nanomaterials can greatly extend the range of control and manipulation that can occur in nanomedicine and other applications.

One interesting recent example is engineered fusion proteins, inorganic-binding peptides conjugated with bioluminescence proteins. The fusion proteins can be used as bioimaging molecular probes both targeting minerals (through fluorescence labeling) and monitoring the rate of biomineralization (through induced reactions). (Yuca et al., Biotechnol Bioeng. 2011 May;108(5):1021-30.)

Figure 1. Integrating organic and inorganic materials: graphene sheet sandwiched in the hydrophobic interior of a phospholipid

Another example (Figure 1) is graphene sheets sandwiched in the hydrophobic interior of a phospholipid. The phospholipid layers of the membrane electrically isolate the embedded graphene from the external solution which means that the composite system could be used in the development of biosensors and bioelectronic materials. (Titov et al., ACS Nano. 2010 Jan 26;4(1):229-34.)

Consciousness only exists as a human construct

It is quite possible that consciousness may not be an objectively definable phenomenon, but rather a convenient illusion created by humans to provide a context for understanding reality. While machines such as CT scans and MRIs measure human cognition, it may not be possible to measure the direct qualities of consciousness. Philosophers and others have pointed out that consciousness may be a subjective quality arising from the operation of the brain.

One reason that a more detailed look at consciousness may be interesting is in the contemplation of non-human intelligence. Given the aspect of subjective qualia surrounding the label consciousness, it might be insulting to non-human intelligence to be referred to as having consciousness, the more objective attribute ‘self-aware’ being preferable. If human consciousness does not exist, non-human consciousness would be even less likely to exist.

Longevity genomics paper retracted

On July 22, 2011, a high-profile longevity genomics paper published in Science in July 2010 was retracted. The paper, ‘Genetic Signatures of Exceptional Longevity in Humans,’ was the work of Thomas Perls and Paola Sebastiani (Boston University). The initial study had been revised per editorial concerns that arose last year, but has now been retracted possibly due to issues related to the replicatability the findings.

The revised study results were presented by the team at the American Aging Association meeting in June 2011. These data featured nine single SNP associations (versus two previously), and linked 281 SNPs to signatures for exceptional longevity (versus 180 SNPs previously). The overall conclusion remained unchanged - that

centenarians, while having the same disease mutational profiles as non-centenarians, have other specific aspects to their genetic profiles which indicate a signature for exceptional longevity

Towards an epistemology of citizen science

Now that citizen science in the health domain is becoming more established, it is relevant to scale it up to tackle larger projects. Several things can be done such as the definition and introduction of liability and oversight models that would be the analogue of the traditional IRB (institutional review board), and the professionalization of participant roles in the study ecosystem such as that of the study manager.

A more subtle issue is to develop an epistemology of citizen science. This would provide a structure and context for exploring the knowledge that is derived from citizen science. One question is whether new kinds of knowledge are being formed through group collaborations such as wikipedia and health social networks. Another question is characterizing the differences (if any) in the types of knowledge generated by traditional medicine, self-experimentation, and health collaboration communities.

Practical applications in anti-aging

One nice aspect of aging conferences is that there are usually a few gems of information that can be applied immediately in humans. Several actionable solutions were highlighted at the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA (conference summary), in the areas of pharmaceuticals, nutrition, lifestyle, exercise, and fasting.

In summary, hypertension drug losartan may help sarcopenia, the healthier fats and antioxidants in walnuts, blueberries, and nectarines may facilitate health, hot tubs may reduce blood pressure, endurance exercise is better for older adults, and protein restriction may be the best form of caloric restriction.

In detail...

• In pharmaceuticals, the prescription drug losartan (an angiotensin receptor blocker) is typically used to treat hypertension and high blood pressure. It may also have anti-aging benefits in combating sarcopenia and frailty by improving muscle remodeling and grip strength.

• In nutrition, recommendations were for walnuts, blueberries, and nectarines. Walnuts are good because they are the only nut containing a significant amount of alpha-linolenic acid (ALA), and because they are mainly composed of polyunsaturated fatty acids (PUFA, both omega-3 and omega-6) rather than monounsaturated fatty acids (MUFA), as most other nuts. Blueberries continue to be an important suggestion for anti-aging. They contain anthocyanins, antioxidants which may prevent inflammation and help to improve brain signals and memory function. The 2011 Blueberry Health Study reported that individual cognitive performance improved 1% over a one year period from consuming one half cup to two cups of blueberries per day. Necatrines (and acai) also have antioxidant properties and have been found to reduce oxidative damage and improve longevity in Drosophila melanogaster (Boyd, Free Radic Biol Med, 2011).

• A lifestyle anti-aging remedy was found in nonhuman primates. Heated hydrotherapy, e.g.; jacuzzis, two times a week for 30 minutes at 39-41 degrees C, induced heat shock response (which declines with age) and increased production of heat shock proteins 70 and 90 which resulted in reduced blood pressure.

• Exercise is always a good anti-aging improvement especially since 60% of U.S. adults over 60 have insufficient physical activity. Type II fibers (fast-twitch) are most vulnerable to aging so instead of trying to improve these, for older adults, it is better and easier to maintain Type I fibers associated with endurance exercise. For example, 70-80 year olds running 2-3 miles a few times a week had the glucoregulation profiles of sedentary adults in their 20s.
  

• Fasting, especially amino acid (e.g.; protein) deprivation, before chemotherapy and surgery was found to help in reducing injurious impact.

World supercomputing capability more than triples

In a breath of good news for Japan this year, RIKEN's supercomputer "K Computer" vaulted to the top slot in world supercomputing in June 2011 as tracked by Top 500 Supercomputer Sites.

Remarkably, capability more than tripled to over 8 petaflops per second (8 quadrillion calculations per second, measured as the Maximal LINPACK performance achieved), after supercomputer performance had been asymptoting at close to 1 pf and 2 pfs for the last three years (Figure 1). China's Tianhe-1A at the National Supercomputing Center in Tianjin was in second place, and the US's Jaguar Cray at Oak Ridge National Lab in third.

The capacity tripling constitutes obvious potential benefits to scientific computing, the realm of applications for which supercomputers are used. It is hoped that these kinds of quantitative changes may eventually lead to qualitative changes in the way other problems are investigated, for example how the brain works.

Figure 1. Source: Top 500 Supercomputer Sites

Synbio revolution: biology is the engineering medium

Synthetic Biology 5.0: The Fifth International Meeting on Synthetic Biology, was held at Stanford University June 15-17, 2011. There were 700 registered attendees, 400 posters, and 100 people at peak on the live ustream video broadcast. Synthetic biology (synbio) is the design and construction of new biological entities such as enzymes, genetic circuits, and cells or the redesign of existing biological systems. Engineering principles are applied to harness the fundamental components of biology; biology is an engineering medium.

The status of the synbio field was discussed, how

• it is possible to synthesize an enzyme but not design a protein
• it is possible to synthesize a chromosome but not predictably engineer a circuit
• it is not known how to engineer on a whole genome basis
• it is not known how to interface with inorganic material (e.g.; man-made substances)

One of the biggest areas of current activity in synbio is metabolic engineering, optimizing genetic and regulatory processes within cells to increase the cells' production of certain substances, for example biofuel generation. Techniques range from directly deleting and/or overexpressing the genes that encode for metabolic enzymes to targeting the regulatory networks in a cell to efficiently engineer the metabolism.

Theme #1: Biology is finite
The overarching theme that emerged from the conference is that

biology is detailed, systemic, dynamic, and complicated, but in the end finite

The question then becomes ‘how long will it take’ to do certain things. Synthetic biologists have buckled in for the long-term, focusing on the biology revolution being to this century what the computer revolution was to the past century. To be more precise (and congruent with engineering), it may not be that all biology is in the end finitely discoverable and explainable, but rather that even in systems ecologies, manipulations can be conducted effectively within bands wide enough to reach goals and limit risk. An example of a classic problem illustrating the trade-offs of synbio is whether it would be better to engineer wheat that impedes rust or a virus that eats the rust on the wheat.

Theme #2: 3 main approaches to synbio: extend E. coli capacity, biomimicry, de novo synthesis
A recurring theme at synbio conferences is the diversity of approaches. There are three main types, first is extending engineering capacity in the building blocks of nature that are already synbio workhorses such as E. coli and yeast. Second is canvassing nature for additional functionality, including cataloging the natural world and the entire human metabalome, peptidome, virome, bloodome, etc. Third is de novo engineering from scratch to build necessary functionality in minimal cells/minimal genomes, including the possibility of supplementing nature-provided parts with newly created amino acids and nucleotide base pairs. An example that considers the trade-offs between approaches is engineering up from minimal cells versus engineering down from organisms that already have some of the needed functionality, for example up from E. coli or down from rhizobia, soil bacteria that have nitrogen fixation (biosynthesis) capability.

Grand challenges
There was an attempt to define some of the grand challenges in synbio, which can be categorized as building block, biology characterization, and systems engineering challenges.

Building block challenge

• Synthesize the full genome of a bacterium
• Design and manufacture a minimal cell
• Design bacteria that hunt and kill tumors
• Enhance the photosynthesis process in plants
• Expand model organism culturing capability from E. coli and yeast to the vast number of microbes

Biology characterization challenges

• Understand the key interactions of band gap material in a cell
• Understand the multigenic epistasis of thousands of genes in heterologous systems
• Understand contact from a cellular basis
• Figure out how to create programmatic control of complex development steps (for example, body plan)
• Define how many changes are necessary to create a new species

Systems engineering challenges

• Define designs and specifications (that can be predictably and reliably verified and constructed)
• Improve challenges in the synthesis, design, analysis of existing systems
• Engineer for the open systems of the real world, beyond closed-environment bioreactors
• Improve tools for computer-based circuit, genome, and chromosome design
• Develop theoretical frameworks to scale synbio to bigger questions; envision the future beyond putting a lot of small pieces of DNA together more quickly and cheaply
• Develop effective means to design, generate, and test recombinant organisms in the environment (for example, injestable bacteria in humans like an organism that cures cancer or probiotic bacteria for Crohn’s disease)

Conference report: interventional anti-aging

The focus of the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA was emerging concepts in the mechanisms of aging.

Many usual topics in aging were covered such as dietary restriction (DR), inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration.

Newer methods like microRNAs and genome sequencing were employed to investigate gene expression variance with aging and genetic signatures of longevity.

Aging as a field continues to mature including by using a systems approach to tracing conserved pathways across organisms, sharpening definitions of sarcopenia, frailty, and healthspan, and distinguishing interventions by age-tier (early-onset versus late-onset).

A pre-conference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions.

Conference talks applied the biology of aging in a translational manner to intervention development.

• Using an individual’s own stem cells to regenerate organs for transplantation and as a cell source for cellular therapies could be a powerful near-term solution to disease.
  
• Several proposed interventions were pharmaceutical, myostatin inhibition, losartan, JAK pathway inhibitors, and enalapril for frailty and sarcopenia, and metformin to promote Nrf2 anti-inflammation response.
  
• In dietary restriction, protein restriction was found to be better than general calorie restriction. Short-term fasting may be helpful in chemotherapy, surgery, and acute stress, simultaneously increasing the killing of cancer cells by chemotherapy, while improving the survival of normal cells.
  
• Immune system interventions remain elusive, although statins may help to improve cellular-senescence promoted bacterial infection.
  
• Engineered enzymes may be useful in lysosomal catabolism.
  
• Dietary restriction mimetics, most promisingly involving TOR (TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.

More details: Meeting Summary preprint.

Engaging personal health collaborators

Health social networks have been growing steadily over the last few years – the leader PatientsLikeMe now has 100,000 patients and 500 conditions listed. Numerous other personal health collaboration communities exist.

The health social network segment is now getting mature enough to expand its focus from deep, specific interest communities, often around disease, to also thinking about going mainstream to attract hundreds of thousands, and eventually millions of people to explore a wide variety of physical and mental performance areas.

At the first Quantified Self conference held in Mountain View CA May 28-29, 2011, an important area of discussion was regarding the best ways to build and engage community participation, whatever the topic. Here are some ways that large numbers of individuals might be enticed to come together for self-directed health exploration:

• Crowd-sourcing each piece of the value chain: the data, the questions, the financing, and the analysis
• Technology-mediated tools to make participation easy and automated
• Fun: making participation fun by using the contemporary ubiquity of gaming principles in persuasive behavior and group activity design
• Market-tools: using market design principles such as scarcity, value exchange, and currency (e.g.; reputational, points, monetary, etc.) amassing for community stickiness
• Enhancement-focus: offering many topical and aspirational frames (e.g.; performance enhancement) since not everyone is interested in “health” or “wellness”
• Low-friction interactions funneled into tiers of increasingly committed participation: making it very easy for potential participants to like, join, interact, and commit to health communities

Just as people have hobbies, exercise, and entertainment activities of preference, so too may they have health collaboration focus areas in the future.

Time malleability

There are differences between the conceptualization of time in computing systems and the human conceptualization of time. At the most basic level in computing, time is synonymous with performance and speed. At the next level in computing, there are “more kinds of time” than in the human and physics perspective where time is primarily continuous. In computing, time may be discrete, synchronous and asynchronous, absolute and relative, and not elapsing at all.

Concurrency trend in contemporary computing
Computing is now making time even more malleable as a side effect of the quest to develop concurrent systems (multi-cores and multi-processors, and cluster, grid, and cloud computing), in at least four ways. One technique is using functional languages such as Haskell, LISP, Scheme, Clojure, and F# where sets of items and processes may not need to be temporally ordered. A second method is enhancing existing computer languages with new commands like ‘happensbefore’ and concurrency control mechanisms like ‘lock free queues’ to manage multiple threads of code operating simultaneously. A third means is creating new models with less time dependency like MapReduce which automatically parallelizes large data problems into finding all possible answers (‘map’), and determining relevancy (‘reduce’). A fourth technique is extending alternative models such as clock free methods and asynchronous computing and restructuring problems to be distributed for more expedient resolution.

Building intelligent systems
The building of intelligent systems is a special problem in computing. There are many approaches ranging from attempts to model human thinking, including the conceptualization of time, to attempts to building intelligent systems from scratch. All models might benefit from incorporating biological time models such as temporal synchrony, the notion of a high-level background synchronization of processes.

Conclusion
Computers are already great time-savers. Computing approaches to contemporary problems like concurrency and building intelligent systems are increasing the ability to manipulate time. Ultimately, humans may be able to greatly extend the control of time, for all intents and purposes creating more time.

From “The conceptualization of time in computing”

Advances in cytosolic drug delivery

Nanoparticles (particles smaller than 100 nm where materials display different properties than at the bulk state) are frequently used in nanomedicine for drug delivery and other purposes. The sophistication and specificity of nanoparticle use is growing, particularly for delivering drugs past the lipid bilayer barrier of the cell wall to the inside of cells (cytosolic drug delivery) where they can target biophysical processes more easily. Two advances focus on cytosolic drug delivery, using light and peptides to break the endosomes (carrying vehicles) to release drugs directly into the cytosol.

1) Light-mediated endosomal breakage
One advance is in the development of nanoparticles (size-tunable (30-200 nm) highly monodispersed mesoporous silica nanoparticles) that can be loaded with a variety of compounds and released into the cytosol via light-mediated endosomal breakage, as illustrated in Figure 1 (Febvay et al, Nano Lett, 2010).

Figure 1: Nanoparticle cargo discharge through light-activation.

2) GALA peptide endosomal breakage
A second advance is in cytosolic drug delivery with nanoparticles using a peptide, GALA, to encourage endosomal breakage. GALA (comprised of repeating sequences of Glu-Ala-Leu-Ala) mimics the function of viral fusion protein sequences that mediate escape of virus genes from endosomes (Nakase et al, Methods Mol Biol, 2011).

Anti-aging research developments in rapamycin, sirtuins, and stem cells

The Third Bay Area Aging meeting was held at Berkeley on May 8, 2010.

One highlight was the emperor’s new clothes statement “Maybe C. Elegans (e.g.; worm) is not the correct model organism for human aging!”

A variety of research was presented, with four themes amongst the most interesting:

1. Role of rapamycin in preventing inflammation
Rapamycin (more technically known as the mammalian target of rapamycin (mTOR)), has long been examined in aging since it is a protein that regulates a range of cellular behavior including growth, proliferation, motility, and survival. Initially hoped to be useful in treating cancer, rapamycin later turned out not to kill tumors due to systems biology; when mTOR is given and the TOR pathway is knocked out, the ERK pathway is upregulated instead.

However new research presented by Remi-Martin Laberge (Buck) shows that there is hope for rapamycin in the context of inflammation prevention. The normal process is that DNA damage response leads to NF-kB (a protein controlling DNA transcription) activation which leads to IL-6/8 (inflammation-related proteins) buildup, but with an mTOR introduction of rapamycin, instead IL-1a (an immune-response regulator) is obtained which prevents inflammation.

The prevention of inflammation is thought to be critical in anti-aging as many aging pathologies start with inflammation which later escalates to waste-build up and tissue break-down. This work is part of ongoing SASP (senescence-associated secretory phenotype) research by the Campisi lab (recent papers on p53 and p38MAPK).

2. Role of recently discovered SIRT7 in oncogenesis
Matt Barber (Stanford) presented work regarding a recently discovered SIRT (Silent Information Regulator) protein. SIRT7 is a chromatin-associated protein and site-specific histone H3 K18 deacetylase. There is a potential connection with SIRT7 and oncogenesis in that SIRT7 interacts with ELK4 (a pathway upregulated in cancer) to suppress a tumor suppressive gene expression network and helps stabilize aggressive cancer phenotypes.

3. Enhanced stem cell therapies
Randy Ashton (Berkeley) showed research regarding the increased ability to dopaminergiacally pattern hESCs to facilitate regenerative therapies for Parkinson’s disease. This was accomplished by making a protein important in neural development, sonic hedgehog, more sensitive through polyvalency.

4. Protein homeostasis and proteasome activity necessary for long lifespan
Brett Robison (Buck) presented work suggesting that normal proteasome function is required for full lifespan in yeast. The proteasome is an important location for waste degradation in cells. Aging cells showed impaired protein homeostasis and decreased proteasome function but it is unclear if this is cause or effect. Theodore Peters (Buck) also showed that maintaining protein homeostasis is important for healthy aging.

Genomic polymorphisms trigger phantom limb pain and synesthesia

Well-known cognitive neuroscientist V.S. Ramachandran (“Phantoms in the Brain”) has been extending his original phantom limb pain research into new realms over the last several years, facilitated by the advent of new tools such as fMRI and genomic analysis.

It turns out that phantom limb pain is related to other anomalies such as synesthesia, a ‘mis-wiring’ of the senses such that stimulation to one sense results in an experience in another (for example, someone may see Monday as red). In all of these cases, there is an overabundance of neural connections in the brain. Genomic polymorphisms prevent these connections from being pruned normally.

Synesthesia is 7-8 times more common in artists, which begs the question of creativity measurement. A synesthete’s depiction of the world he or she sees may look like creativity to non-synesthetes, but is it reporting or creativity from the synesthete’s viewpoint? Synesthetes of the same type would need to assess creativity.