Devon Ehnes

Cancer as a disease and its surgical treatment was acknowledged as early as 1600 B.C., and several times after that. However, although the term oncology was coined by the Greek physician Galen in the second century, it primarily consisted of surgical treatments until halfway through the 20th century. The so-called "age of chemotherapy" arose after World War II when medical professionals and scientists were studying series of chemicals that soldiers had been exposed to during the war in an effort to understand their effects and to identify protective measures against these effects. One of the chemicals they were studying, the mustard gas derivative nitrogen mustard, was found to interfere with white blood cell proliferation, and when tested on animals with lymphomas (cancers of the lymph nodes), they went into remission. This laid the groundwork for further studies of chemical treatments for cancer, and in 1947, Dr. Sidney Farber showed that a chemical known as aminopterin could successfully treat pediatric leukemia in human children, albeit temporarily, opening the floodgates for oncological drug discoverydrug discovery.

Because of the targeting issues presented in drugs that are already available, it is clear that successful precision oncology will require massive development of new drugs or alterations of existing drugs to improve targeting. However, this is no small feat. Even in terms of current targeted therapies, drugs are not yet available for many cancer drivers, at least partly due to the tremendous cost in both money and time. In addition, the genomic signature from one part of the tumor measured at a certain time point likely does not represent other parts or different time points of tumor development. With regard to drug developmentdrug development, this dramatically increases the amount of drugs that would need to be available to treat different kinds of cancer, presenting a huge hurdle for precision oncology.

Since the late 19th century different versions of targeted chemotherapy have been introduced, including radioactive iodine treatment for thyroid cancer in the 1940s, and, following the 1962 identification and characterization of the estrogen receptorestrogen receptor, the development of Selective Estrogen Receptor Modulators (SERMs) in 1977 to treat estrogen receptor positive cancers. The first successful molecular targeted therapy, meaning it targets cancer cells at the level of the molecular signaling pathway, was with the drug imatinib. This drug treated a unique kind of leukemia: chronic myelogenous leukemia cause by the Philadelphia chromosome. In this kind of cancer, the Philadelphia chromosome produces an overexpressed fusion protein called BCR-Abl tyrosine kinase, which does not occur in normal cells. Imatinib is an inhibitor that specifically targets cells expressing BCR-Abl tyrosine kinase, thus suppressing the growth of Philadelphia chromosome-positive cells with less harm to normal cells. This major landmark in targeted molecular therapeutics led to the rapid development and approval of many new drugs, both small molecules and immunotherapeutics (antibodies). However, many drugs initially approved were found to lack efficacy or to have unbearable side effects, and were removed from the market. Despite these early setbacks, many more successful targeted therapies have been introduced.

Since the late 19th century different versions of targeted chemotherapy have been introduced, including radioactive iodine treatment for thyroid cancerthyroid cancer in the 1940s, and, following the 1962 identification and characterization of the estrogen receptor, the development of Selective Estrogen Receptor Modulators (SERMs) in 1977 to treat estrogen receptor positive cancers. The first successful molecular targeted therapy, meaning it targets cancer cells at the level of the molecular signaling pathway, was with the drug imatinib. This drug treated a unique kind of leukemia: chronic myelogenous leukemia cause by the Philadelphia chromosome. In this kind of cancer, the Philadelphia chromosome produces an overexpressed fusion protein called BCR-Abl tyrosine kinase, which does not occur in normal cells. Imatinib is an inhibitor that specifically targets cells expressing BCR-Abl tyrosine kinase, thus suppressing the growth of Philadelphia chromosome-positive cells with less harm to normal cells. This major landmark in targeted molecular therapeutics led to the rapid development and approval of many new drugs, both small molecules and immunotherapeutics (antibodies). However, many drugs initially approved were found to lack efficacy or to have unbearable side effects, and were removed from the market. Despite these early setbacks, many more successful targeted therapies have been introduced.

According to the company website, development of cell-based steaks is more sustainable, cruelty-free, and can reducedreduce the transmission of food-borne illnesses.

In an article published on June 2, 2018 by, the Institute for Electrical and Electronic Engineers (IEEE) weighed the benefits and challenges of using cells (as opposed to plant products) to develop animal-free meat. They noted that using cellular components can allow developers to control proportions and types of fats in the final products, allowing them to control the flavor and nutritional content. Also, since the final product would actually be meat, it wouldcould be more palatable and convenient to consumers. However, a major hurdle for scientists looking to generate meat from cells is what to put into the nutrient mixture which coaxes the cells toward muscle fibers. Currently fetal bovine serum is used, a product derived from fetal calves in a costly and unsustainable process. These are problems that have already been considered by several cell-based meat companies including Memphis Meats, Just, Inc., and SuperMeat, and others, suggesting one of the main challenges for HigherSteaks will be catching up to other more established companies.

Higher Steaks is a London-based cellular agriculture startup founded in December 2017 that is using new, undisclosed cell culture techniques to develop steaks and other cell-based meat products. It was founded by chemical engineer Benjamina Bollag and stem cell biologist Stephanie Wallis.

According to the company website, development of cell-based steaks is more sustainable, cruelty-free, and can reduced the transmission of food-borne illnesses.

As of June 2018, although there is a basic website available, there is no evidence that the company has yet secured seed funding, filed any patents, or has developed any product. Although they are new, they are far from the only company looking to develop clean meat from cells. A recent article from the Institute for Electrical and Electronic Engineers (IEEE) weighed the benefits and challenges of using cells (as opposed to plant products) to develop animal-free meat. They noted that using cellular components can allow developers to control proportions and types of fats in the final products, allowing them to control the flavor and nutritional content. Also, since the final product would actually be meat, it would be more palatable and convenient to consumers. However, a major hurdle for scientists looking to generate meat from cells is what to put into the nutrient mixture which coaxes the cells toward muscle fibers. Currently most research uses fetal bovine serum, a product derived from fetal calves in a costly and unsustainable process. These are problems that have already been considered by several cell-based meat companies including Memphis Meats, Just, Inc., and SuperMeat, and others, suggesting one of the main challenges for HigherSteaks will be catching up to other more established companies.

While it has not been stated what edge the company will bring to the development of cell-based meat, founder Benjamina Bollag's research background gives way to some speculation. First, after earning her Master's degree, she went to work for fragrance and flavoring company Firmenich where she developed new flavoring molecules, suggesting she may be able to contribute to more accurately flavored steaks. Following this, she worked for 3D printing and additive manufacturing company Stratasys, where she worked to solve "solidification problems", leading to speculation she might attempt a 3D manufacturing model, which recently gained some traction in Australia.

Aranex Biotech, Inc. is a Canadian agriculture startup based in Ireland. Founded in April 2015, Aranex Biotech is working to make "hypoallergenic peanuts."

Aranex Biotech, Inc. is a Canadian synthetic agriculture startup based in Ireland. Founded in April 2015, Aranex Biotech is working to make "hypoallergenic peanuts." At its 2015 initiation, Aranex Biotech, Inc. was provided with seed funding by IndieBio, a subgroup of American venture capital group SOSV. CEO Chloe Gui then presented the concept at the 2015 IndieBio EU Demo Day, drawing the interest of another SOSV accelerator RebelBio. University College Cork, where Aranex Biotech laboratories are based, has partnered with IndieBio as part of an accelerator program for up and coming food developers.

Peanuts allergies are one of the most prevalent types of food allergies, and are capable of causing life-threatening anaphylactic reactions. Peanut allergies are commonly diagnosed in children less than 2 years old, and are the food allergy least likely resolve with age. A recent review by Bunyavanich et al. looked at diagnoses of peanut allergies between 1997 and 2007 and found that in children under the age of 18, the prevalence of the peanut allergy more than doubled, and since then, the upward trend has continued, an estimated twenty percent. Experts predict that this number will continue to rise, though the exact reason for this increase is unclear. There have been some studies to suggest that lifestyle may play a role. A 2012 study found a higher incidence of food allergies in children living in cities compared to more rural areas.

According to Aranex CEO Chloe Gui, most other companies that are working to reduce peanut allergies have been focused on controlling the RNA or proteins from the culprit genes. She thinks the novelty of her company is that they are looking to develop genetically modified plants using CRISPR-Cas9 gene editing to completely remove three major allergenic genes from the plant. As of 2018, there were no available patents on their process or products, but Chloe Gui states that they plan to begin field test and clinical safety trial and seek regulatory approval starting in 2018.

Aranex Biotech plans to market their products specifically to farmers, with an ultimate goal of replacing traditional peanut crops. They also plan to work with companies that consume large quantities of peanuts to set up partnerships. They have already begun talks with Mars and the Hershey Company.

From Chloe Gui's 2015 IndieBio EU Demo Day

According to Aranex Biotech, one of their biggest hurdles will be whether they can continue to procure funding depending on whether CRISPR developed peanuts are considered GMO crops. There are different criteria in different countries that determine whether crops are labeled "GMO". Additionally, should Aranex's products be labeled GMO, they may face the same scrutiny and backlash that many GMO crops have faced, making it difficult for them to break into the market.

In 1990, scientists identified the primary allergen in peanut plants, opening the doors for research into treatment and prevention. Since then, a handful of other genes have also been elucidated, and scientists are closer to understanding why peanuts evoke such a strong allergic reaction. Some food scientistscientists have moved toward attempting to attenuate the allergens, making peanut products safer for consumers with allergies. A food bioprocessing company known as Alrgn Bio developed an "product cleansing" enzymatic process that uses the enzyme Alcalase to inactivate the proteins in various peanut food products. Another group of food scientists led by Peggy Ozias-Akins used small interfering RNAS (siRNAs) to genetically modify peanut plants. Her experiments yielded plants with reduced levelsHere ofare twosome of the primarythose allergens.endeavors:

• A food bioprocessing company known as Alrgn Bio developed an "product cleansing" enzymatic process that uses the enzyme Alcalase to inactivate the proteins in various peanut food products.
• Another group of food scientists from the University of Georgia led by Peggy Ozias-Akins used small interfering RNAS (siRNAs) to genetically modify peanut plants. Her experiments yielded plants with reduced levels of two of the primary allergens.
• Plant biologist Hortense Dodo runs agricultural biotech IngateyGen, which uses genetic engineering to generate hypoallergenic peanuts for commercial sale. Although most of their products are modified peanuts, their company interest in to improve human health and nutrition, and they are also working on a fortified yam.

Aranex Biotech, Inc. is a Canadian agriculture startup based in Ireland. Founded in April 2015, Aranex Biotech is working to make "hypoallergenic peanuts."

Peanuts allergies are one of the most prevalent types of food allergies, and are capable of causing life-threatening anaphylactic reactions. Peanut allergies are commonly diagnosed in children less than 2 years old, and are the food allergy least likely resolve with age. A recent review by Bunyavanich et al. looked at diagnoses of peanut allergies between 1997 and 2007 and found that in children under the age of 18, the prevalence of the peanut allergy more than doubled, and since then, the upward trend has continued, an estimated twenty percent. Experts predict that this number will continue to rise, though the exact reason for this increase is unclear. There have been some studies to suggest that lifestyle may play a role. A 2012 study found a higher incidence of food allergies in children living in cities compared to more rural areas.

Peanut allergies have created substantial social difficulties. Because of the potential severity of the reaction, many schools have banned all kinds of peanut products from schools, while psychology experts have proposed that children with food allergies have a more difficult time making friends and assimilating into their class. Other studies show that there is an economic impact: families that have one or more members with a food allergy spend on average $1,000 more on food each year. Outside of social difficulties, studies have found that food allergies including peanut allergies can lead to growth defects in children, and a study on quality of life found that parents of children with food allergies suffered more anxiety and a decreased quality of life compared with parents of allergy-free children.

In 1990, scientists identified the primary allergen in peanut plants, opening the doors for research into treatment and prevention. Since then, a handful of other genes have also been elucidated, and scientists are closer to understanding why peanuts evoke such a strong allergic reaction. Some food scientist have moved toward attempting to attenuate the allergens, making peanut products safer for consumers with allergies. A food bioprocessing company known as Alrgn Bio developed an "product cleansing" enzymatic process that uses the enzyme Alcalase to inactivate the proteins in various peanut food products. Another group of food scientists led by Peggy Ozias-Akins used small interfering RNAS (siRNAs) to genetically modify peanut plants. Her experiments yielded plants with reduced levels of two of the primary allergens.

Aranex Biotech, Inc. is a Canadian agriculture startup based in Ireland. Founded in April 2015, Aranex Biotech is working to make "hypoallergenic peanuts".

Balletic Foods is a Silicon Valley based startup founded in 2017. On November 1, 2017, the company secured its first round of seed funding from an undisclosed resource.

According to their website, they are interested in "refining" existing technology of isolating muscle stem cells to make cell-derived meat to reduce greenhouse emissions from the processs and to produce the highest quality meat.

As of May 2018, they had not yet disclosed the names of their managing staff, and they had not filed patents for new products or protocols.

According to their Twitter account, the company participated in a Clean Meat Panel in San Francisco on May 31, 2018, as a part of an industry conference known as Cultured Meat Symposium, leading to speculation that the new CEO may be former Google software engineer Robert Yaman, who was credited in the panel roster as the CEO of a "clean meat startup still in stealth mode".

Precision oncology is a type of personalized medicine in which a cancer patient's tumor is profiled using NexGen sequencing in order to identify specific targetable genetic alterations. These alterations can then be treated with drugs that can uniquely act on them, thus increasing positive treatment outcomes. To date, the most well-understood treatment for various types of cancer has been a combination of surgical resection of the tumor combined with a regimen of chemotherapeutic treatementtreatment. However, in addition to surgical limitation for resection (some tumors cannot be resected without causing more damage to the patient, known as inoperable tumors), this method of treatment has many adverse effects associated with it. Specifically, many major chemotherapeutic agents target cellular processes associated with cell cycle, which means the cytotoxic agents can have negative affects not only on cancerous cells, but on all rapidly-dividing cells including hair, nails, skin, stomach lining, and immune cells. This unintended consequence can leave the patient weak and susceptible to secondary infections, which can be fatal. In the 1990s, when oncology began to rapidly expand as a field, almost all cancer treatments outside a few successful targeted therapies, most other chemotherpeuticschemotherapeutics were based on killing cycling cells.

Because of the many issues with traditional cancer treatments, drug developers have shifted toward targeted therapeutics that aim to recognize unique characteristics of cancer cells, therefore sparing most healthy cells. While this has been an effective advance that has resulted in fewer, more managablemanageable side effects for cancer patients, the inherent differences between the many types of cancers has made it impossible to generate effective targeted drugs that work for all cancers.

Cancer as a disease and its surgical treatment was acknowledged as early as 1600 B.C., and several times after that. However, although the term oncology was coined by the Greek physician Galen in the second century, it primarily consisted of surgical treatments until halfway through the 20th century. The so-called "age of chemotherapy" arose after World War II when medical professionals and scientists were studying series of chemicals that soldiers had been exposed to during the war in an effort to understand their effects and to identify protective measures against these effects. One of the chemicals they were studying, the mustard gas derivative nitrogen mustard, was found to interfere with white blood cell proliferation, and when tested on animals with lymphomas (cancers of the lymph nodes), they went into remission. This laid the groundwork for further studies of chemical treatments for cancer, and in 1947, Dr. Sidney Farber showed that a chemical known as aminopterin could successfully treat pediatric leukemia in humanshuman children, albeit temporarily, opening the floodgates for oncological drug discovery.

The definition of targeted chemotherapy has evolved over the last three decades as we have learned more and more about what distinguishes cancer cells from healthy cells. It can be broadly defined as a chemotherapeutic agent aimed at unique characteristics of cancer cells. The earliest version of this was hormone therapy, . The earliest groundwork for hormone therapy was laid in 1847, when Thomas Beatson noticed that rabbits that had had ovariectomies (ovary removal) stopped producing milk, establishing a functional link between the breast and ovary tissues. He went on to treat a patient with recurring breast cancer with a bilateral ovariectomy, and reported that that patient went into complete remission and survived for 4 years after the surgery. Although the underlying hormone Estrogen was not yet identified, and his rationale for the surgery turned out to be incorrect, Beatson laid the groudwork for modern day hormone therapy.

Currently, comprehensive treatment using precision oncology has been limited to clinical trials, and success in using these approaches have been mixed. Various retrospective studies have touted the potential success of precision oncology, showing that between 80% and 90% of patients tested have potentially actionable genomic alterations. However, a retrospective study is one that looks backwards to examine an outcome that is established at the start of the study, meaning they have substantial bias. Moreover, the definition of "actionable" across these studies varied substantially, giving some doubt to these optimistic estimates, and demonstrating the novelty of this process. The first prospective study aimed to use molecular profiling to assign matched therapy did not show favorable outcomes for the matched group. However, this study was plagued by serious methodological issues. Widely known as the SHIVA study, it represented the first randomized study using precision oncology. The trial studied 195 patients with any metastatic solid tumor cancer, and follwedfollowed them for nearly a year after treatment. Patients were randomly assigned to receive either molecularly targeted agents that were already developed and approved for other uses and thus used "off-label". The agents were assigned either on the basis of the molecular profile of the tumor or based on the physician's choice (representing the randomized control). Although the study leaders themselves touted this as a failure, saying it demonstrated that precision medicine isn't as promising as previously thought, and that off-label uses of drugs should be discouraged, other scientists have challenged this, pointing out that most cancer patients have multiple actionable mutations and are unlikely to respond to monotherapy (treatment with a single agent). They also pointed out one of the most concerning issues of the study: patients randomly assigned to targeted therapy were treated using the SHIVA predefined algorithm, whereas the control group was assigned therapy by the physician who could take into account a patient's comorbidities. Despite the negative results of the study, this first clinical trial opened up a dicussiondiscussion among the medical and scientific communities as to how to continue to improve these trials in the future.

While the SHIVA trial took a broad approach, other trials have focused on developing precision oncology in a specific type of canercancer. One such group of researchers conducted a trial the called the BATTLE trial: Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination. This trial went through both Phase I and Phase II trials, and like the SHIVA trial, also had methodological issues followed by insignificant changes in disease control rate compared to control after 8 weeks of monitoring. However, Phase I of this trial successfully demonstrated the feasibility of repeat tissue biopsies, a necessary capability for long-term molecular-based cancer treatment. It also demonstrated the success of biomarker-directed assignment of treatment regimens based on trial results, incorporating adaptive randomization toward regimens with more efficacy compared to controls, a cornerstone of precision medicine. This group's most recent trial, entitled BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer, focused on the efficacy of the various treatment regimens for the approximately 20% to 25% of patients with advanced non–small-cell lung cancer, whose tumors contain a mutation in the GTPase gene KRAS. In this population, which represents the largest ever molecularly defined subset of non-small cell lung cancer patients, initalinitial tests using the drug sorafenib has shown a promising preliminary activity. However, end results of the trial demonstrated no clear significant in disease control rate in any of their treatment groups.

Although there have been substantial gains in the availibilityavailability of molecularly defined targets as a result of the incorporation of genomic sequencing of tumors, much of the hope for transitioning from the current standard of cancer treatment into one of precision medicine relies heavily on a broadening molecular marker testing that

either hasn't yet been developed or is poorly optimized. Because of this issue, drugs, which have been developed using shortcuts on the basis of low standards, can be approved on accelerated basis. The desire to put forth new treatments despite this low threshold undermines the ability of scientists and clinicians to adequately test their hypotheses. ReminiscientReminiscent of the boom in targeted therapeutics in the 1990s, this introduces the risk of prematurely replacing existing effective therapies with more costly ones, merely on the basis of a preclinical or retrospective rationale, and unproven or weak preliminary evidence.

As the price of genomic sequencing has come down, more and more people have been able to access this technology to have their own genome sequenced. Concomitantly, a trove of legal and ethical concerns have erupted. In order for the precision medicine to become the standard of care, a substantial amount of genomic data must be collected from a significant number of people, representative of all the variations of different populations across the world. This need has introduced questions of privacy and ownership of the data. One of the primary concerns with privacy of genomic information for reasons of discrimination. For example, there are fears that people could be denied health or life insurance because markers in their genetic profiles suggest increased susceptibility to degenerative diseases such as Alzheimers. Premiums for these kinds of insurance poliespolices are currently subject to change based on age and health, but because of the novelty of this kind of genetic information, few countries have legislation regarding how genomic information can be used and accessed.

This new field doesn't only lead to risks for patients. Because of the increased use of genomics to identify new treatments for not only cancer, but also many other diseases, doctors have begun to wonder how this will affect their practice. A 2013 study found more than 50 cases in which patients sued their physicians for malpractice relateingrelating to treatment or recommendations based on genomic results, reiterating the need for better legislation governing the use of genomic information to treat and diagnose illnesses of many kinds, before personalized medicine can move forward.

In theory, precision medicine can eliminate failed treatments, repeated efforts, multiple hospitalizations, and can even prevent disease by using preventive measures against genetically identified disease risk, ultimately reducing healthcare expenditures. However, at its current stage, development and pefectionperfection of precision medicine requires substantial investment in research, legal developments, and security infrastructure. Although the cost of genome analysis has come down over the last two decades, the depth of sequencing required (which comes at a higher cost that commercially available kits like 23amdme23andme) combined with the repeat sequencing that would be necessary during patient treatment means that this treatment remains costly and is may not be feasablefeasible to less funded medical facilitesfacilities in underserved areas or countries in turmoil. Because of cost, many of the most cutting edgecutting-edge institutions are developing in-house testing, which helps to reduce cost, however this approach has received criticism because it introduces variation in assay standardization and data interpretation, as we don't currently have a single validated protocol that can be used across institutions.

In addition to cost issues surrounding the actual genomic testing, the cost of drug development and testing is substantial. As demonstrated by the SHIVA trial, it might be difficult to simply use readily aviailableavailable drugs to treat mutations identified by sequencing. The more likely scenario is that over the course of many more years, we can use sequencing to identify new mutations in different types of cancer and work to develop drugs to treat them. However, it is estimated that the cost of developing a single new pharmaceutical is in excess of $2.5 billion, a steep pricetagprice tag for individualized medicine.

As a tumor grows and spreads, it develops different needs that activate multiple signaling pathways at different times. This means that the "actionable mutation" can be different in early cancer than in later stages. For example, clear cell renal cell carcinomas and non-small cell lung cancers both exhibited distinct mutational signatures during early carcinogenesis compared with cancer progression and between different tumor subclonessub-clones. Another study used single cell sequencing to show that tumors from two breast cancers developed point mutations continuously during cancer progression, but copy number aberrations were only acquired early on in tumorigenesis. Next-generation sequencing shed light on the clonal selection processes that govern these newly acquired mutations, most of which favor cell survival and drug resistance, and highlighted the importance of considering evolution in cancer, and the difficulty it can present for finding appropriate drugs to treat tumors with evolving subclonessub-clones.

The gut microbiome possesses copious metabolizing xenobiotics, or small molecules that are foreign to the human body, and research is increasingly showing that these can be important for the regulation of many cellular processes, and can sometimes interfere with the efficacy and safety of cancer drugs. One such drug known as irinotecan, used to treat colon cancer, becomes SN-38, an active topoisomerase inhibitor in the body. SN-38 can then be metabolized by host liver enzymes and subsequently lose its activity. However, bacterial β-glucuronidase found in the gut hydrolyzes and reactivates SN-38G in the large intestine, leadig to intestinal damage and diarrhea. Therefore, a deep undetstanding of microbiota in each patient is crucial in each patient to increase drug efficacy and reduce adverse side effects.

The gut microbiome possesses copious metabolizing xenobiotics, or small molecules that are foreign to the human body, and research is increasingly showing that these can be important for the regulation of many cellular processes, and can sometimes interfere with the efficacy and safety of cancer drugs. One such drug known as irinotecan, used to treat colon cancer, becomes SN-38, an active topoisomerase inhibitor in the body. SN-38 can then be metabolized by host liver enzymes and subsequently lose its activity. However, bacterial β-glucuronidase found in the gut hydrolyzes and reactivates SN-38G in the large intestine, leading to intestinal damage and diarrhea. Therefore, a deep understanding of microbiota in each patient is crucial in each patient to increase drug efficacy and reduce adverse side effects.