Algorithmically Tailored Immunotherapy: The Amazon Method of Curing Cancer?

“Customers who bought this item also bought…” Well, in the case of therapies for life-threatening diseases, Amazon’s familiar trope does not sound too helpful since it will frequently, and quite predictably, list “all of the above,” especially before insurance benefits have run out. And yet, it is a highly valuable if nascent computational concept, even though a long road still lay ahead before it may start to limit wasteful and disheartening trial-and-error in clinical reality.

The first effective oncological immunotherapy was approved just a few years ago. Today, patients with advanced skin cancer receive this therapy where medication supports the immune system in its struggle against cancer. Data analysis of several thousand skin cancer patients who were originally predicted to have only a few months to live shows that in about one-fifth of them, even two to three years after immunotherapy, tumors show no signs of return. This turned into a medical sensation that was all the more impressive as these drugs showed results not just with skin cancers but also with other types of malignancies, and now immunotherapeutics are approved also for lung, bladder and kidney cancers, adding more variants almost by the day.

The downside is that immunotherapy is effective only in about 20 percent of patients with most cancers. There are varieties, such as colon cancer, that are largely resistant to immunotherapy. Again, bioinformatics holds considerable promise to change this picture, since colorectal cancer is one of the most common types, with 1.4 million new cases per year world-wide. 

To be able to predict which combination of immunotherapy and standard therapy would be effective in a given patient, researchers breed in the lab mini organs, so-called organoids, which have been surgically removed from cancerous tissue. These organ-like structures are small tumors in their own right with the patient’s own genetic footprint. They are therefore ideal for testing the effect of various medications on the immune system of a specific individual. Data from these extensive tests will then be fed into a computer model that should ultimately predict which combination therapy would be most effective for each patient. A first review of a comprehensive study of over 600 colorectal cancer patients in Cancer Genome Atlas showed that infiltrating antibody cells of a tumor are very different depending on its origin, patient’s genetic predisposition, and tumor environment.

The number of mutations also varies greatly from tumor to tumor – from several hundred to several thousand per patient. This heterogeneity of one and the same tumor could signal a turning point in the search of cancer immunotherapy that fits all patients. It appears that hardly two colon cancer patients have identical mutation profiles. Therefore, breeding individual organoids that react very differently to treatment is essential.

Manipulating organoids by genetic and pharmacological means yields a lot of knowledge about drug treatment of tumors that is required to make them respond to immunotherapy. Technology for breeding organoids exists only since a few years and can be combined with high-throughput screening technology, which allows accurate characterization of organoids and determination of molecular profiles.

In order to derive targeted information for immunotherapy of cancers from bioinformatic analyses, an additional step is required: creation of tailored mathematical simulation models to process data feeds. This permits meaningful simulation of a wide variety of combination therapies. The number of possible combinatory permutations is enormous: in recent years, at least 70 new cancer drugs were approved, in addition to conventional chemotherapy still in use, and at least six new immunotherapeutic drugs. Algorithmic models can, in principle and depending on their quality, distill individualized combination therapies for each patient, creating a form of targeted precision medicine based on detailed knowledge of the specific mutation profiles of each tumor.

Key to that approach is the supply of the greatest possible amount of data from different clinical trials. Individual patient profiles need to be combined with data of similar patient groups and information about the medication; after evaluation, specific therapy recommendations could be expected to result. This process of advanced combinatorics is ultimately similar to the way Amazon evaluates customer interest from past purchases of individuals and larger groups; in oncology, scientists are aiming at specific recommendations for customized cancer therapy. Human oncologists would be overwhelmed with distilling and interpreting such data floods with any degree of accuracy, but combinations of AI and BigData methods can be expected to show the pathway toward the most effective therapy – not only for each type of cancer but also for each individual’s situation. With immunotherapy cost currently around $150,000-240,000 per year (and rising rapidly), accurate prediction as to what therapy combinations will be effective for which patient is not only key to survival for the individual but also for an already heavily strained health care system. The choices involved in the process inescapably demand answers to that most inconvenient of political questions: how much is temporary human life worth?

Bands Who Code: Massive Attack’s Mezzanine Now on DNA

1998’s Mezzanine was one of the legendary albums of Massive Attack; its single release “Teardrop” became a worldwide hit. To celebrate its twentieth anniversary, the British trip hop band will now have its album archived in DNA for eternity, using technology developed at ETH Zurich. Robert Grass, professor at the Laboratory for Functional Materials Engineering at ETH Zurich, claims this form of data storage enables archiving ‘for centuries or millennia.’

First, Grass and his colleague Reinhard Heckel, a former ETH researcher now at Rice University, translated the digital soundtrack to genetic code: while information is stored on an optical medium or hard drive in a sequence of zeros and ones, biology saves genetic information in a sequence of the four DNA building blocks A, C, G, and T. To make a data set of this size manageable, they compressed the music file to 15MB using Opus technology, a compression method qualitatively superior to, say, popular mp3.

A U.S. company currently manufactures 920,000 short DNA molecules that store all the data of Mezzanine. These molecules are then infused into 5,000 nanometer-sized globuli by Zurich company Turbobeads, an ETH Zurich spin-off.  The nanoparticle beads may be preserved in a small vial as a dispersion in water with virtually unlimited durability.

It is possible to extract the DNA from those beads anytime and read the music file saved on it by means of DNA sequencing in order to play it on a digital device. Although the method for this is rather involved, millions of copies of the information can be made at minimal expense once it is stored.

Grass and Heckel developed the technology three years ago. At that time, ETH scientists immortalized, as a kind of proof of feasibility, the text of the Federal Charter of 1291, a foundational document of the Swiss Confederation, in DNA. Now their method is used commercially as well. The music album by Massive Attack is the second largest file ever stored in DNA. The only larger one in existence is a file collection of more than 200MB that Microsoft has stored on DNA. DNA storage capacity is pegged at 215 petabytes per gram, or some 100 million movies…

Food Innovations in Sustainable Urban Development

Vertical Farming: Agro-Startups from Silicon Wadi Conquer European Urbanism

The concept of urban farming is, of course, not new. With the carbon footprint of essential produce increasingly of concern to urban consumers with purchasing power, agro startups, although only peripherally involved with IT or biotech, are fast becoming hot items. Berlin may not sound like a natural choice for a young Israeli agro-startup, but one of the most promising experiments in advanced urban integration indeed took root there before it spread out to Paris, London and Copenhagen. Infarm is, in a manner of speaking, ‘sprouting out-of-the-box.’ ‘Microgreens,’ the shoots of salad vegetables such as arugula, celery, beetroot, etc., picked just after the first leaves have developed, contain up to 40 times more vital nutrients than mature plants. Microgreen economics of indoor production contrast remarkably with economics of conventional farming. Microgreens are quick to grow, moving from seed to feed in just one to three weeks depending on plant variety, and with an incredible yield-to-space ratio, offering a perfect solution for urban living with increasingly little room or time for a garden, as they require minimal expense, time and effort for a highly expeditious healthy harvest of organic greens. Functional requirements are very modest: access to good light means no more than a well-lit bench indoors, a tray or other suitable shallow container, water, and a growing medium. This model also offers near-total independence from climate: fresh living greens for salads, sandwiches, soups and garnishes are easy crops to grow year-round.

Infarm, founded 2013 by an Israeli couple from Tel Aviv and one partner’s brother in an Airstream mobile home, laid the foundation for an increasingly fashionable urban gardening scene in metropolitan Europe with a staff that grew to well over 100 to date and includes biologists, engineers, programmers and management talent. Together, they have spawned more than 70 ‘vertical farms’ in Berlin restaurants, warehouses, and supermarkets. Infarm provides and operates under leasehold agreements the vertical farming boxes with sensors that constantly record and monitor data, including pH, temperature, light, density of nutrients, and other factors. The system uses AI to learn and optimize conditions on location. Edeka, Germany’s largest national supermarket chain, has stocked its outlets in Berlin and Hannover with urban farming boxes that enable customers to purchase after work some incomparably freshly harvested greens or other produce for dinner. A 5000 square meter hall at the outskirt of Berlin houses City Hub Farm where farming boxes and their technology are manufactured. In early 2018, the company announced that it had raised from investors €20 million, which is expected to fund also expansion into other metropolitan areas: Paris-Nanterre is expected to feature a 100 square meter indoor farm at a Metro supermarket by end of 2018. By mid-2019, 1,000 indoor farms are expected to be operational across Europe. First imitators, the sincerest form of flattery, have emerged already, proving business model viability and growing demand. Some new vertical farming technologies use no soil and up to 95% less water, although metrics, comparability of data and claims are disputed and critiqued by some.  

Urban Aquaculture

Aquaculture, a fancy term for fish farming, has had its ups and downs over recent decades as reservations against the quality of farmed fish grew steadily – at least among those consumer segments that were not compelled to make purchasing decisions primarily on price. Urban aquaculture includes the farming of aquatic organisms, including fish, mollusks, crustaceans and aquatic plants within the urban environment: rivers, ponds, lakes, canals, but also and especially indoors – the nearer to the consumer, the higher efficiency and the better. Urbanizing aquaculture is not a new concept: oceanic habitats are becoming less hospitable, with water temperatures and acidity rising, dead zones growing, and mass extinction of fish and coral species looming in an uncomfortably near future. Farmed fish, on the other hand, is raised in conditions so dirty that constant antibiotics and other chemicals must be supplied for it to grow to consumable size. Urbanization requires making recirculating aquaculture systems small enough to run anywhere on a municipal water source, putting a vision of jacuzzi-sized tilapia tanks on every roof within very realistic reach. It is a concept not only capable of yielding at least 100 pounds of fish per person per year, but also using fish waste to grow hydroponic plants floating on a foam sheet on the water surface in the same tank, producing lettuce in six weeks.

As an obvious consequence, urban aquaculture will transcend the hobby stage if, and only if, it can be facilitated to transcend a circle of activist enthusiasts by integrating it meaningfully and thoughtfully into advanced urban architectural planning and developing adaptation kits for properties that do not have easily convertible facilities. While urban farming and aquafarming may be capable of relatively practicable integration in urban or suburban sprawl, it is still extremely difficult to show the same for metropolitan living in even moderately sophisticated high-rises and limited apartment sizes dictated by disproportionate real estate costs per square foot. Here, only centralized, communal facilities are realistic – which, in turn, require board approval and involve the possibility of obstruction. Therefore, truly ‘domestic’ fish farming in a metropolitan setting would seem feasible only under exceptional circumstances and especially in townhouses or rare rooftop apartments. But urban-domiciled centralized facilities integrated in supermarkets or specialty stores are nonetheless a promising option that still provides extreme freshness with manageable compliance and quality control procedures. It is probably fair to say that architecture and organizational matters and procedures are more of an obstacle to metropolitan urban aquaculture than technology or safety inspections.

But neither vertical farming nor aquaculture are likely to cover more than a fraction of needed supply, and have to be balanced to coexist with traditional food supplies from conventional sources and locations, thus only gradually reducing sustainability concerns. Nonetheless, small-scale urban aquaculture has a wide range of benefits for the future evolution of urban agglomerations. Legal foundations exist and do not present particular or unfamiliar challenges.

Now That's a First – “World’s Best Island Resort” Shuttered for Environmental Reasons

Philippines close Boracay Island for six-month cleanup

Populist regimes are beginning to discover environmental protection as a fertile signature issue. It is increasingly where the votes are. At least in small baby steps and far from everywhere. While Poland’s logging of Europe’s last remaining (and UNESCO-protected) primeval woodland of Białowieża has incurred a final judgment imposing a €100,000 daily fine by the ECJ, Philippine president Rodrigo Duterte has discovered that “When nature fights back, it does so with a vengeance.” His government imposed - and surprisingly upheld - a ban on open-pit mining and starts to target polluting steel mills.

 

Now, popular Boracay Island in the Philippines was closed to visitors for six months due to massive environmental problems. Starting April 26, authorities no longer permitted tourists to land on the island. Some 600 security forces were deployed in total to secure and enforce the visitors ban. Administering the “closure” alone amounts to a logistical nightmare.  

 

The quarantine period until November is to be used to visit the island to fix the worst issues and perform a clean-up mission. Many hotels, restaurants and shops on Boracay are said to have, inter alia, channeled their sewage including feces for years simply into the sea. President Duterte is said to have personally ordered the closure and to have called Boracay, where vacationing tourists spent 21 million nights in 2017 alone, a “cesspool” - ordering his environmental secretary to “clean the goddamn thing.”

 

Boracay, about 300 kilometers south of Manila, was voted “best island in the world” by Conde Nast Traveler in 2017. About 40,000 locals live on the island, most of whom earn their livelihood from tourism. Real estate development has been another curse of popularity. The ban is estimated to cost tourism revenues of some $2.75 million as 15% of the country’s 6.5 million tourists visit Boracay. The Philippine government plans to provide emergency financial aid in the amount of some $109 million, although it has not clarified how these funds will be distributed.

Can Serendipitous Discoveries Save Mankind from Itself? The Case of Plastic-Digesting Enzymes and Bacteria

As a further chapter in my occasional highlight of serendipitous discoveries, teams of scientists from the UK and the U.S. discovered and evolved in Japan an enzyme that can degrade plastic by assisting a bacterium with digesting PET plastics. Ongoing further research promises to put a relatively cheap end to worldwide plastic pollution by recycling it sustainably. As it stands today, PET plastics can survive hundreds of years in the environment and have turned into an increasingly serious and mushrooming burden to major countries and large oceanic regions. Researchers from the University of Portsmouth, UK and the Renewable Energy Laboratory at the U.S. Department of Energy have now discovered, and published in PNAS, a potential solution to this blight by studying and tuning the structure of a natural enzyme that developed on its own in a Japanese waste recycling center. Initial research found that the PETase enzyme assists a bacterium, Ideonella sakaiensis 201-F6, with breaking down or digesting PET plastics. The enzyme structure was then optimized by bioengineering by adding some amino acids. This optimization process resulted in random changes to PETase’s activities and ultimately indeed an altered enzyme that turned out to be significantly more effective than its natural form. The same team now continues to explore the enzyme further to see if PET plastics can be degraded on an industrial scale, and if so, with what side effects. It is entirely possible, indeed likely, that the next few years will yield industrially viable processes to disassemble PET and possibly other plastics back into their original organic building blocks to set in motion a sustainable chain of recycling. Independent scientists not directly involved in this research consider this biodegradability approach clearly promising despite the obvious concerns that the development of the enzyme as possible solution against pollution is still at too early a stage to render a meaningful assessment possible. And that may well be true, but it is also secondary: enzymes are non-toxic, biodegradable and capable of being produced in large quantities by microorganisms, and there is great potential for using enzyme technology to solve society's growing waste and landfill problem by degrading at least some of today’s most commonly used plastics. Even as it may still be necessary to await further developments intended to improve the enzyme, this discovery brings sustainable recycling of plastics within striking distance.