Philippine Journal of Science 148 (S1): 15-32, Special Issue on ISSN 0031 - 7683 Date Received: 19 Mar 2019

Creating a Roadmap for Building a Sustainable Genomics Facility in the

Alexander T. Young*

Philippine Genome Center University of the Philippines Diliman, Quezon City 1101 Philippines

Genomics, , and high-throughput technologies provide a means to create breakthrough solutions for a remarkably wide diversity of fields – including medicine, agriculture, fisheries, livestock, and biodiversity. Significantly, the precision of genomics and DNA enable the creation of applications that are specifically optimized for the Philippines. Dissemination of these technologies throughout the country is accelerated by genomics facilities that provide access to core technologies. However, there are significant scientific and business challenges for creating a sustainable genomics facility in the Philippines. The historical successes and challenges of genomics and high-throughput technologies are reviewed, which point to potential solutions for creating a sustainable genomics facility in the Philippines.

Keywords: bioinformatics, drug discovery, functional genomics, genomics, high-throughput DNA

INTRODUCTION systems in order to find new applications that benefit society. In conjunction with the technological advances in biology New and exciting advances in genomics and high-throughput and engineering, advances in computational sciences have technologies are revolutionizing the application of biological enabled the daunting task of interpreting the massive amounts sciences. Advances in engineering, microfluidics, robotics, of data that these technologies generate (bioinformatics). and miniaturization have created machines that can rapidly The ability to profile thousands to millions of biological determine the DNA sequence of an organism’s genes or molecules in a massively parallel fashion promises to create the entire genome. Similar advances in miniaturization new biological insights that can lead to better medicines, have created machines that can rapidly test the activity of agriculture, fisheries, forensics, and molecular diagnostics. thousands of biological samples (high-throughput assays). All of these new technologies are available or being High-throughput assays can be used to screen libraries of developed at the (PGC). thousands of chemical compounds for the identification of new drug molecules that combat disease (high-throughput The PGC was created by the Philippine government with screening). Technologies that simultaneously profile major funding coming from the Department of Science thousands of RNA transcripts to measure gene activity and Technology and Commission for Higher Education (transcriptomics), proteins (proteomics), metabolites “to create a deeper understanding and judicious application (metabolomics), and microorganisms (microbial community of advanced knowledge and emerging technologies in profiling/metagenomics) in response to disease, drugs, or the genomics and bioinformatics for the benefit of Filipinos environment promise to unravel the complexities of biological and the rest of humanity.” Located at the in the University of the Philippines (UP) Diliman *Corresponding Author: [email protected] campus, the PGC is housed in a newly constructed 5,600-m2

15 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines facility with the construction of a second 4,500-m2 building Table 1 depicts the top five best-selling prescription medicines underway. While PGC is part of the UP system, the PGC twenty years ago in 1998 when the Human Genome Project is intended for use by all Philippine entities – including was actively underway. Since drug development takes an public and private universities outside of the UP system, average of seventeen years – from initial basic research government agencies, industries, non-governmental discovery to product launch (Westfall et al. 2007) – Table 1 organizations, and collaborating institutes and companies reflects the trend towards mechanism-based drug discovery in other countries. in the 1980s as our understanding of molecular biology became more sophisticated. Hence, the most successful Research and development (R&D) at the PGC currently drugs revolved around the modulation of specific cellular engages in four programs: 1) health; 2) agriculture, targets that have been determined through basic research to livestock, and fisheries; 3) biodiversity and ethnicity; and be associated with specific disease pathways. For example, 4) computational genomics and systems biology. The PGC, the top-selling drug in 1998 was the peptic ulcer drug Prilosec the high-throughput technologies it offers, and the domain (omeprazole; approved in 1988), which lowers stomach acid expertise of numerous people can promote sweeping by blocking the action of a gastrointestinal proton pump. advances in these fields to benefit the Philippines and Table 1 also illustrates the use of biomarkers such as high society. The ability to identify and quantify thousands of serum cholesterol or high blood pressure as a metric for molecular biomarkers through genomics, transcriptomics, the use of cardiovascular drugs to treat atherosclerosis or proteomics, metabolomics, and other emerging “omics” hypertension. Statins like simvastatin (approved in 1992) technologies can create precision technologies that are treat atherosclerosis by modulating the enzyme involved tailored and optimized for Filipino patients, Philippine in cholesterol biosynthesis. Calcium channel blockers like crops, Philippine fisheries, and the Philippine ecosystem. amlodipine (approved in 1990) and angiotensin-converting This article discusses the successes and challenges of enzyme inhibitors like enalapril (approved in 1984) are used genomics and high-throughput technologies in the past to treat hypertension because both drugs modulate target and present, with a particular emphasis on how these proteins that regulate blood pressure. Previous drug discovery technologies can impact the Philippines in the future. was based upon relief of symptoms without an understanding of biological mechanism or drug targets. For example, the mechanism by which aspirin relieves pain and fever was not understood until it was later discovered that aspirin binds to HEALTH the target protein cyclooxygenase, an enzyme involved with Paradigm shifts in healthcare are already seen from the the synthesis of inflammatory prostaglandins. Human Genome Project and DNA sequencing technologies. The Human Genome Project became a platform for the These include paradigm shifts in the way that pharmaceutical discovery of new drug targets. Drug targets represent entire companies conduct R&D to discover new prescription generations of drug classes (e.g., statins, ACE inhibitors, medicines and paradigm shifts in the way that physicians calcium channel blockers). In 2006, shortly after the treat patients. The impact of the Human Genome Project and completion of the Human Genome Project, it was estimated DNA sequencing technologies on human healthcare can be that all 21,000+ known drugs (of which 1,357 were of illustrated by comparing the top-selling prescription drugs unique classes) exert their therapeutic effects by affecting before and after the Human Genome Project (Tables 1 and 2).

Table 1. Top 5 selling prescription drugs of 1998. Brand Generic name Therapeutic area Target Platform Biomarker 1998 sales name (billion) Prilosec Omeprazole Ulcers and gastric Gastric H+/K+ ATPase Small molecule PHP 210.73 esophageal reflux disease (proton pump) (USD 3.9761) Zocor Simvastatin Hypercholesterolemia HMG-CoA reductase Small molecule Serum PHP 209.09 cholesterol (USD 3.9450) Prozac Fluoxetine Depression Serotonin transporter Small molecule PHP 149.04 hydrochloride (USD 2.8120) Norvasc Amlodipine Hypertension Calcium channel Small molecule Blood PHP 136.50 besylate pressure (USD 2.5750) Vasotec Enalapril Hypertension Angiotensin converting Small molecule Blood PHP 127.20 enzyme pressure (USD 2.4000) Source: Med Ad News (May 1999)

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Table 2. Top 5 selling prescription drugs of 2017. Brand Generic name Therapeutic area Target Platform Biomarker 2017 sales name (billion) Humira Adalimumab Arthritis; Crohn’s disease, TNF Protein therapeutic, PHP 976.6 ulcerative colitis alpha human monoclonal (USD 18.427 billion) antibody

Rituxan Rituximab Non-Hodgkin’s lymphoma; CD20 Protein therapeutic, CD20-positive PHP 489.6 chronic lymphocytic chimeric human- B cells (USD 9.238) leukemia; rheumatoid murine monoclonal arthritis (RA) antibody Revlimid Lenalidomide Multiple myelomas as Cereblon Small molecule PHP 433.9 maintenance therapy (USD 8.187) following autologous hematopoietic stem cell transplantation; transfusion- dependent anemia Enbrel Etanercept Arthritis; ankylosing TNF Protein therapeutic, PHP 417.9 spondylitis; plaque psoriasis chimeric dimeric (USD 7.885) TNF receptor – immunoglobulin Fc fusion protein Herceptin Trastuzumab HER2 overexpressing HER2 Protein therapeutic, HER2- PHP 394.4 breast cancer; HER2 humanized overexpressing (USD 7.441) overexpressing metastatic monoclonal antibody breast cancer gastrointestinal cells adenocarcinoma Source: Philippidis (2018) only 266 targets encoded by human genes (324, including drug target is associated with a disease) followed by pathogen targets) (Overington et al. 2006). This represents lead identification/optimization (wherein new chemical only a small fraction of the estimated 19,000 genes in the entities or protein therapeutic lead investigational drugs human genome (Ezkurdia et al. 2014). Hence, the Human are identified that modulate that target), animal studies (to Genome Project creates the possibility of identifying test for efficacy and toxicity), and finally clinical trials for thousands of new drug targets and therapeutic approaches proof of concept and approval for use in patients. Prior to to disease. By 2017, there were an estimated 667 targets the human genome project, 99% of target identification encoded by human genes (893, including pathogen targets) came from academia and not from the pharmaceutical for all drugs approved in the USA (Santos et al. 2017). While industry (Caskey 1997). Pharmaceutical companies were much of the 2.5-fold increase in estimated drug targets can primarily chemistry-driven companies that would screen be attributed to more sophisticated categorization systems for lead compounds that acted upon targets followed by from the same authors of the previous study, an authentic testing in animal models and clinical trials (Figure 1a). five-fold increase in the number of protein kinase and For the first time, the Human Genome Project enabled protease targets was noted in a period of only ten years. pharmaceutical companies to actively participate in Notably, these novel protein kinase targets for breakthrough the front end of the drug discovery process through cancer drugs were identified because they were encoded by an industrialized approach to target identification and cellular proto-oncogenes with DNA sequence similarity to validation using robots and high-throughput technologies. oncogenes in the genomes of tumor-inducing retroviruses In the late 1990s and 2000s, pharmaceutical companies (Bishop and Varmus 1989). began entering into major multibillion-peso partnerships with genomics companies that were sequencing the The Human Genome Project initiated a change in the human genome and performing functional genomic and way pharmaceutical companies conduct research along high-throughput studies to identify and validate drug the drug discovery value chain. The drug discovery value targets (Figure 1b). For example, in 1998, the German chain is a way to visualize the sequential series of steps pharmaceutical company Bayer AG entered into the in drug development that pharmaceutical companies largest corporate alliance in the history of have followed for decades (Figure 1). These steps consist through a USD 465 million partnership with the US of target identification/validation (wherein a potential genomics company Millennium Pharmaceuticals. The

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Figure 1. Drug discovery value chain and evolving complementary roles of academia, genomics companies, and pharmaceutical companies. goal of this genomics-based drug discovery alliance was in 2017 are the oncology drugs Rituxan (rituximab) and to identify novel validated drug targets for cardiovascular Herceptin (trastuzumab). Both drugs are monoclonal diseases, cancer, osteoporosis, pain, liver fibrosis, antibodies that use the antigens that they are directed hematological diseases, and viral infections using against as molecular biomarkers to guide physicians. genomics, transcriptomics, and proteomic technologies. In contrast to physiological biomarkers such as serum cholesterol or blood pressure, molecular biomarkers are Today, pharmaceutical companies have active in- present on specific cells and tissue. Rituxan and Herceptin house programs in genomics, functional genomics, are prescribed to cancer patients whose tumors have been proteomics, and metabolomics to discover new drug shown to be positive for the biomarkers CD20 or HER2. targets. Significantly, pharmaceutical companies partner Rituxan and Herceptin have dramatically improved overall with many universities, institutes, and biotechnology survival rates with a significant reduction in side effects companies in their drug discovery efforts. Realizing (compared to conventional chemotherapy) because these the contribution of basic research to drug discovery drugs specifically destroy CD20-positive and HER2- applications, pharmaceutical companies have established positive tumor cells. Conventional chemotherapies from research facilities in many cities with academic centers of the past create severe toxic side effects because they non- excellence. For example, in the Boston area which is home specifically kill all rapidly dividing cells – not only cancer to Harvard and MIT, the pharmaceutical companies Abbvie, cells but also normal, rapidly-dividing cells such as hair AstraZeneca, Merck, Novartis, Pfizer, Sanofi, and Takeda follicle stem cells and gastrointestinal cells (resulting in Pharmaceutical have all established pharmaceutical R&D hair loss and severe gastrointestinal illness). Hence, the centers there. The future of the PGC could involve active use of molecular biomarkers to stratify and select drug- collaboration with pharmaceutical companies throughout responsive patients for use with oncology drugs that target the entire drug discovery value chain from lab-to-clinic, the specific etiologic cause of their cancer represent the as new translational research-based approaches to drug new shift towards targeted patient-specific therapies and discovery are rapidly becoming adopted (Figure 1c). precision medicines. The use of genomic biomarkers based upon DNA sequence Post- Human Genome Project Drugs and the Rising polymorphisms (variations) of specific genes to guide therapy Use of Genomic Biomarkers to Guide Drug Therapy is embraced by the US Food and Drug Administration. In through Precision Medicines 2008, the US Food and Drug Administration listed 22 Today’s top five best selling prescription medicines approved genomic biomarkers to guide the prescription of (Table 2) illustrate the genomics-driven shift towards specific drugs. Today, that number has increased to over precision medicines and translational research approaches 250 approved genomic biomarkers (FDA 2018a). Table 3 to drug discovery. Table 2 also illustrates the rising is a select list of the top-selling prescription drugs that use prevalence of protein therapeutic monoclonal antibodies, genomic biomarkers to guide therapy. A large number are which are a direct result of the knowledge of human targeted oncology therapies indicated for patients harboring antibody sequences. Cancer therapies, in particular, are tumors overexpressing specific gene products (HER2, experiencing a burst of new drug classes and therapeutic EGF receptor) or gene rearrangements (BCR-ABL, PDGF approaches. Two of the top five prescription medicines

18 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines receptor). The targeted oncology drug Gleevec (imatinib) is single nucleotide polymorphisms in genes encoding notable for pioneering the use of a biomarker to determine enzymes involved in drug metabolism are used to guide the mechanism, target, and selection of patients. This strategy the dosage of drugs. Individuals with genetic variations resulted in the drug’s unprecedented success and rapid in enzymes such as those in the cytochrome P450 system approval to treat chronic myeloid leukemia (CML). In 2017, (encoded by CYP2C19 or CYP2D genes) or uridine the US Food and Drug Administration approved seven new diphosphate glucuronosyltransferase (UGT) markedly drugs employing targeted therapy approaches with the use of metabolize drugs differently from the general population molecular biomarkers (FDA 2018b). A number of companies so that the expected plasma concentration of drugs is either now offer molecular diagnostic tests to guide therapy for too low or too high at the recommended doses. Hence, the specific tumor types. For example, the Oncotype Dx Breast oncology drug Tasigna (nilotinib) and the antifungal drug Cancer kit marketed by Genomic Health interrogates 21 Vfend (voriconazole) use a patient’s UGT1A1 and CYP2D genetic biomarkers from breast cancer patients to guide genotypes as guides for dosage. The selective serotonin treatment options (Sparano et al. 2015). Recently, a genomics reuptake inhibitor and anti-depression drug Prozac analysis and long-term follow up analysis of breast cancer (fluoxetine) inhibits the activity of patients with CYP2D6 patients reveal a greater number of etiologic subtypes variants, which affects the toxicology profile of other drugs of breast cancer based upon molecular biomarkers and that the patient may be taking. Therefore, CYP2D6 testing is correlated to relapse (Rueda et al. 2019). These data could recommended. Even the classic anticoagulant drug warfarin someday be used to predict which patients that have already – approved in 1954, and requires frequent monitoring of been treated are in risk of relapse and which patients can be patients to prevent bleeding side effects – now benefits from assured of lower risk of recurrence. toxicology biomarker testing through CYP2C9 genotyping. Patient-specific medicines are now being tested for One exciting development is the exploration of preclinical cardiovascular diseases. For example, patients with a toxicology biomarkers by the US FDA. Preclinical toxicology single nucleotide polymorphism in an adenyl cyclase gene biomarkers will place toxicity testing further upstream in may have reduced risk of mortality from coronary heart the drug discovery value chain. Investigational drugs are disease events when treated with the investigational drug currently tested for toxicity by a set of well-developed and dalcetrapib, a cholesteryl ester transfer protein inhibitor highly regulated assays that have changed little over time that raises serum high-density lipoprotein (HDL) (Tardif (e.g., the Ames test for DNA mutagenesis, cytochrome P450 et al. 2015). High serum HDL levels have been associated enzyme tests for drug clearance, and animal tests). Despite with reduced coronary heart disease. Dalcetrapib actually the increased throughput in identifying lead compounds, failed to show any clinical benefit in a large 15,871 patient toxicity tests can be performed on only a limited number of clinical trial (Schwartz et al. 2012). A 6,000-patient, leads per year. The high cost of animal studies and chemical multi-institutional phase III clinical trial is currently being synthesis of compounds necessarily places toxicology testing conducted to test the hypothesis that a subset of patients toward the back end of the drug discovery process. The use with the specific adenyl cyclase genotype responds of molecular toxicology biomarkers further upstream in the favorably to targeted dalcetrapib therapy (Pfeffer et al. drug discovery value chain creates the exciting possibility 2018; ClinicalTrials.gov Identifier: NCT02525939). that toxicology testing becomes one of the primary screens for lead investigational compounds – and not just a backend Investigations from the PGC Cardiovascular Genetics Study screen for compounds that were selected primarily on the Group reveal population-specific genetic determinants of basis of potency against a target. High potency does not HDL-C, and that differences in HDL-C levels are seen necessarily translate into a better drug. For example, Bayer’s across ethnic groups with Filipinos having a high prevalence Baycol (cerivastatin) was the most potent cholesterol- of low HDL-C (Cutiongco, pers. comm.). Polymorphisms lowering HMG-CoA reductase inhibitor but was later in five genes are associated with low HDL profile among withdrawn from the market because its tremendous potency Filipinos. The PGC Cardiovascular Genetics Study Group created toxic side effects in the muscle and kidney. also found some useful biomarkers for predicting response to commonly used cardiovascular drugs among Filipinos. Biomarkers as developmental tools for translational Thus, genomic studies in the Philippines are already research. Targeted oncology therapies such as Gleevec pharmacogenomically stratifying the Philippine population, (imatinib) and Herceptin (trastuzumab) laid the which could result in future patient-specific therapies that groundwork for translational research approaches to are therapeutically optimized for Filipinos. drug discovery and pioneered the use of biomarkers in drug development. The use of a common biomarker as Toxicology biomarkers to guide drug dosage. The United a control throughout every stage of drug development States Food and Drug Administration (US FDA) now guaranteed their unprecedented success as oncology recommends and approves the use of toxicology genomic drugs. Historically, the clinical success rate for oncology biomarkers to guide drug therapy (Table 3). For example,

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Table 3. Select list of FDA-approved biomarkers. Brand Generic Indications Target Platform Biomarker 2017 sales name name (billion) Herceptin Trastuzumab HER2 overexpressing breast cancer, HER2 Protein HER2 overexpression PHP 394.4 HER2 overexpressing metastatic therapeutic, (USD 7.441) gastrointestinal adenocarcinoma humanized monoclonal antibody Sprycel Dasatinib Ph+ CML, BCR-ABL, SRC Small molecule Philadelphia PHP 120.8 Ph+ acute lymphoblastic leukemia family (SRC, kinase inhibitor chromosome-positive (USD 2.28) LCK, YES, responders with alternate FYN), c-KIT, context EPHA2, and PDGFRβ Lipitor Atorvastatin Reduces the risk of MI, stroke, HMG-CoA Small molecule Familial PHP 111.3 revascularization procedures, and reductase competitive hypercholesterolemia (USD 2.1) angina inhibitor (deficiency and/or mutation of receptors for low-density lipoprotein- LDL) Gleevec Imatinib Ph+-positive CML, ALL BCR-ABL, Small molecule Ph+-positive CML, ALL PHP 103.0 PDGFR gene rearrangements PDGFR, c-KIT kinase inhibitor PDGFR gene (USD 1.943) or fusions for myelodysplastic/ rearrangements or fusions myeloproliferative diseases, c-Kit mutations hypereosinophilic syndrome (HES), c-Kit expression and/or chronic eosinophilic leukemia (CEL); systemic mastocytosis (ASM) without the D816V c-Kit mutation Tasigna Nilotinib Ph+ CML IC50-BCR-ABL Small molecule UGT1A1 variants PHP 97.6 (20–60 nM), kinase inhibitor with alternate (USD 1.841) PDGFR (69 nM), context c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM) Tarceva Erlotinib Metastatic non-small cell lung cancer EGFR kinase Small molecule EGFR expression with PHP 60.3 (NSCLC) and pancreatic cancer EGFR kinase epidermal growth factor (USD 1.137) inhibitor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations Erbitux Cetuximab Advanced squamous cell carcinoma EGFR Protein EGFR expression with PHP 51.1 of the head and neck; K-Ras wild- therapeutic, alternate context (USD 0.964) type and EGFR-expressing metastatic human/mouse colorectal cancer chimeric monoclonal antibody Vfend Voriconazole Fungal infections CYP450- Small molecule CYP2C19 variants PHP 22.3 dependent antagonist indicate drug metabolism (USD 0.421) 14-alpha sterol and dosage demethylase (Lanosterol 14-alpha- demethylase) Prozac Fluoxetine Depression and behavioral disorders Serotonin Small molecule CYP2D6 with PHP 8.9 [bulimia nervosa, OCD, premenstrual reuptake pump SSRI alternate context (USD 0.168) dysphoric disorder (PMDD), panic disorder] Selzentry Maraviroc CCR5-tropic HIV-1 infection CCR-5 Small molecule CCR5 chemokine C-C PHP 8.8 antagonist of motif receptor, (USD 0.166) GPCR HIV co- phenotypic and genotypic receptor assays Xeloda Capecitabine Breast cancer, colon cancer Thymidylate Small molecule DPD deficiency for PHP 5.9 synthase prodrug of toxicity biomarker; non- (USD 0.111) 5-fluorouracil metabolizable; leads to toxicity Sources: FDA (2018a)

20 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines leads has been dismal – only 2.8% of drug candidates eukaryotic organisms because of exponentially increased that were 100% effective in blocking cell replication DNA sequencing throughput and dramatically reduced in tissue culture and in reducing tumors in animal costs. Molecular studies on coral bleaching, for example, models were effective in clinical trials (Kamb 2005). have risen since the introduction of NGS sequencers as The problem lay in the disconnect between each of the illustrated by the number of publications on coral reef phases of the drug discovery value chain wherein the biologists, chemists, animal physiologists, toxicologists, and clinicians operated as separate non-communicating silos. Significantly, oncology animal models frequently relied on human tumor xenografts that defined tumors based upon anatomical classifications (e.g., breast cancer, colon cancer) rather than the mechanism of action. Table 4 illustrates how a biomarker provided a common denominator and control for each of the developmental phases for Gleevec and Herceptin, which led to the choice of an animal model. In the case of Gleevec, the activated BCR-ABL protein tyrosine kinase was used as an outcome biomarker in human patients for human disease relevance, as a mechanism biomarker in high-throughput screening for a lead compound, as an efficacy biomarker in transgenic animal models with activated BCR-ABL, and as an inclusion biomarker to select drug-responsive Philadelphia chromosome-positive patients with activated BCR-ABL. Similar levels of target validation were used with HER2 overexpression and protein tyrosine kinase activity in the development of Herceptin.

BIODIVERSITY, AGRICULTURE, FISHERIES, AND LIVESTOCK In addition to healthcare, a surge in genomics-based research activity in areas such as biodiversity, agriculture, fisheries, and livestock will have tremendous long-term impacts for the Philippines. Next-generation sequencing Figure 2. Number of peer-reviewed scientific publications with (NGS) machines enable more academic laboratories the keywords “Coral Reef Transcriptome” in a Pubmed to participate in the sequencing of complicated higher search.

Table 4. Criteria for the target validation of Imatinib (Gleevec) and Trastuzumab (Herceptin). Criteria Gleevec (imatinib) Humira (trastuzumab) Human target data [(9;22) (q34;q11)] chromosomal HER2/neu protooncogene is amplified in 25–30% translocation (Philadelphia of primary human breast cancers and correlates with chromosome) found in leukemia cells of more than 90% a negative prognosis of CML patients results in the creation of Bcr/Abl fusion protein with activated protein tyrosine kinase activity Animal target data Murine bone marrow cells transduced with Amplification of HER2 in NIH3T3 cells Bcr-Abl genes creates a CML-like disease results in neoplastic transformation and when injected into mice tumor formation in athymic mice Target modulation Antisense Bcr-Abl inhibits colony formation of human CML Anti-HER2/neu antibody inhibits cells; treatment of Bcr-Abl-positive human tumor-bearing anchorage-independent growth of mice with a competitive inhibitor neu oncogene-transformed NIH3T3 of Bcr-Abl kinase reduces size and number of tumors cells and inhibits tumor growth of neu oncogene- transformed NIH3T3 cells implanted into nude mice

21 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines transcriptomes (Figure 2). Genomics-based research for our own survival” (UNDP 2017). Transcriptomic and into these scientific fields can create better crops, better microbial community profiling studies of coral bleaching fisheries, better livestock, and better management of the could lead to the development of molecular diagnostics that Philippine biodiversity and natural resources. can rapidly pinpoint sources of anthropogenic pollution before rather than after irreversible bleaching occurs. A The application of genomics technologies to coral genomics-based early warning system would provide a bleaching is an example of a high impact project that low-cost rapid test that would guide policymakers and benefits the Philippines. Philippine coral reefs have the coastal ecosystem managers on how to protect coral reefs. highest biodiversity in the world (Roberts et al. 2002) yet experience the highest threat level to extinction from Another example of how genomics is igniting and human impact (Carpenter et al. 2008). Coral reefs are major changing a long-studied field in the Philippines is resources for the Philippines, creating up to PHP 67.5 billion agriculture. Genome-wide association studies of rice annually (USD 1.35 billion) for the Philippine economy conducted by an international consortium involving from fisheries, tourism, and coastal protection (White et Cornell University, the International Rice Research al. 2000). Coral reef fisheries are a major source of food Institute in Manila, and many others have resulted in a supply for the Philippines and create jobs for over a million bioinformatics database that will aid in the identification small scale fishers (BFAR 1997). Human impact is rapidly of genes that could improve rice such as for drought degrading Philippine coral reefs (Bruno and Selig 2007). resistance or pest resistance (McCouch et al. 2016). Damage to 70% of coral reefs (JICA 2015) and the coast due to human impact resulted in the unprecedented six-month Improving livestock could also be accelerated through government shutdown of the coastal tourist area Boracay genomics-based identification of important traits. For in 2018. Hence, there is an urgent need to monitor and example, the Bill and Melinda Gates Foundation is funding associate coral bleaching to specific sources of manmade the Centre for Tropical Livestock Genetics and Health to pollution. However, according to the Philippine Country utilize genomics tools and selective breeding to improve Director of the United Nations Development Program, “We livestock productivity and resilience in developing countries. lack data and a good understanding on the impact we are Figure 3 illustrates the many activities being performed having on the oceans and how much we depend on them at the PGC, either independently or in partnership with

Figure 3. PGC programs and projects in health; biodiversity and ethnicity; agriculture, livestock, fisheries, and forestry; and computational genomics and systems biology.

22 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines universities and institutes throughout the Philippines of Science and Technology. Moreover, DNA sequencing and in other countries. PGC’s bioinformatics program in and bioinformatics core facilities can obtain fees for computational genomics and systems biology is central services from the many academic laboratories, institutes, to all programs in health; biodiversity and ethnicity; and universities lacking the instruments and technologies and agriculture, livestock, fisheries, and forestry. PGC’s to perform genomics-based R&D. By genomics-based health programs range from dengue virus diagnostics, research, we mean the entire collection of technologies for metabolic disorders, cardiovascular diseases, and cancer. gene-based research – including metagenomics, functional PGC’s biodiversity program ranges from natural products genomics, proteomics, metabolomics, and bioinformatics. discovery, genomics of Philippine flora and fauna, and coral reef diagnostics to forensics and genomics of the Despite the significant cost reductions since the Human many ethnicities in the Philippines. PGC’s program in Genome Project, genomics-based research is still agriculture, livestock, fisheries, and forestry ranges from extremely capital-intensive as it requires expensive the genomics of coconuts, shrimp pathogens, abaca, instruments and the staff to operate them. While grants coffee, saba bananas, sugar cane, and pili nuts, to that can support the instruments and staff for the duration of of dairy cattle. For example, in the coconut genomics the project, the inevitable conclusion of the project and program, molecular biomarkers for traits such as copra the grant that supports it creates challenges in continued yield, early flowering time, oil biosynthesis, mutations support of the huge number of staff hired to run a large in the endosperm, and for insect resistance will be used project like the Philippine Human Genome Project. Grants for marker-assisted selection and breeding of selected and fees for services only provide support for the duration varieties and traits. These programs involve partnership of the programs. with a number of other academic institutes – including In order to examine potential business models for the National Institute of Molecular Biology and sustainable growth, the financial reports of several Biotechnology, the Institute of Biology, UP Los Banos, UP publicly-traded biotechnology companies performing Mindanao, and the University of California San Francisco. comparable services were evaluated.

Product Development CREATING A SUSTAINABLE Figure 4 illustrates the growth of the biotechnology company Celgene Corporation, which achieved profitability GENOMICS FACILITY by developing the drugs Thalomid (thalidomide) and A Philippine genomics facility creates undisputed value Revlimid (lenalidomide) for multiple myeloma. Figure to Philippine society. Numerous laboratories, institutions, 4 illustrates that the annual revenues generated by drug and universities throughout the Philippines that lack the sales almost always exceeded operational expenses. instruments and technologies for DNA sequencing and Thus, net income was almost always positive, resulting bioinformatics can participate in high-impact research in profitability. Profitability sustained the growth of the and development through open access to the PGC. The knowledge transfer radiating throughout the Philippines can create a consortium of academic partners and industrial partners, as well as the creation of satellite genomics facilities throughout the country. The challenge for creating value for a Philippine genomics facility is the ability to achieve sustainable growth. Sustainable growth is needed to reach a critical mass in order to support the diversity of programs that help Philippine society. The challenges are similar to a capital-intensive startup biotechnology company that requires financing to build their product or service before reaching profitability and self-sustaining growth. Instead of venture capital financing, a genomics facility Figure 4. Cash flow for a profitable biotechnology company Celgene benefits from government commitment and funding to Corporation illustrating that annual revenue is greater create the infrastructure and operational staff to run basic than annual expenses resulting in net positive income. core facilities for DNA sequencing and bioinformatics. The acquisition of the company Pharmion resulted Government grants can then support specific programs. in a net loss in 2008. Source: Computed from annual This is being done to a large extent by the Department reports submitted to the US Securities and Exchange Commission.

23 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines company, which in turn supported further R&D. cash and cash equivalents and support over 800 people in the company (Figures 5B and 5C). The way that Genomic While it is not the goal of a genomics facility to develop Health manages to stay afloat while striving to reach products, one possibility is to create a spin-off company profitability is through investors that inject money into the with equity ownership by the genomics facility. The company (Figure 5D) in the belief that they will obtain a genomics facility would obtain rights to a share of profits future return on investment. Investment revenue through and downstream royalties from the spin-off company. For private and public investments through the stock market example, it is possible that a natural products discovery is the equivalent of government investments in genomic project based upon screening of the rich biodiversity of the facilities in exchange for future returns to the country. Philippines’ plants, animals, and microbial communities results in a commercial product sold by a spin-off company. Other commercial products resulting from Corporate Partnerships genomics facilities could be genomics-based molecular A third model for generating sustainable revenue is through diagnostics. For example, the PGC is entitled to royalty corporate partnerships with industry. Industrial companies payments from a gene-based dengue virus diagnostic kit such as those in the pharmaceutical, biotechnology, and developed by UP Manila. The Biotek-M™ Dengue aqua agricultural sectors partner with smaller companies that can kit is the first dengue diagnostic kit that is commercialized provide a technology or service that adds value to the larger by the UP Manila spin-off company Manila HealthTek Inc. company’s product development. For example, Editas Medicine – a platform technology company developing new CRISPR-based gene editing technologies – generates Investment Income both investment income and corporate partnership revenue In contrast to a profitable company, we observed that to support its cash flow-negative deficit spending and Genomic Health – the company that provides genomics- growth (Figure 6). For corporate partnership revenue, based molecular diagnostics services and kits to guide Editas entered into two corporate partnerships with two oncology therapy treatment options – experienced losses of larger companies (Table 5). Juno Therapeutics partnered up to USD 33 million (over PHP 1.6 billion) per year for the with Editas in order for Editas to genetically-engineer T last five years (Figure 5A). However, Genomic Health still cell immunotherapies for Juno using Editas gene editing manages to have over USD 45 million (PHP 2.25 billion) in technology. Allergan partnered with Editas to obtain

Figure 5. Example of how a negative income genomics diagnostic company remains cash positive through investments: A) Genomic Health cash flow; B) cash and cash equivalents; C) number of employees; and D) financing activities. Source: Computed from annual reports submitted to the US Securities and Exchange Commission.

24 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines

Figure 6. Example of how a negative-income platform technology biotechnology company Editas Medicine remains cash positive through corporate partnership revenue and investments: A) Editas Medicine cash flow; B) cash and cash equivalents; C) number of employees; and D) financing activities. Source: Computed from annual reports submitted to the US Securities and Exchange Commission.

Table 5. Editas Medicine corporate partnerships with Juno options to five experimental gene editing therapies for eye Therapeutics and Allergan, and corporate partnership disease. Through corporate partnerships, Editas Medicine revenue. receives significant revenue through a combination of Juno Therapeutics partnership to develop T cell immunotherapies upfront payments, R&D funding, milestone payments, and potential downstream royalties (Table 5). Editas received Collaboration year 2015 an upfront payment of USD 25 million (PHP 2.25 billion) Upfront payment USD 25.0 million from its corporate partnership with Juno Therapeutics, and R&D funding USD 22.0 million an upfront payment of USD 90 million (PHP 4.5 billion) Development milestones payments USD 77.5 million from its corporate partnership with Allergan. The purpose Regulatory milestone payments USD 80.0 million of the USD 25 million upfront payment from the Juno Therapeutics partnership is to provide capital expenditures Commercial milestone within each USD 75.0 million research area and new staff to the partnership project and does not include the budget for R&D. R&D is supported from a separate and Allergan partnership to develop therapies for eye disease additional USD 22 million in financing. In addition, Editas Collaboration year 2017 Medicine will be entitled to receive an additional USD 77.5 million in milestone payments if it achieves certain R&D Upfront payment USD 90.0 million goals. An additional USD 88 million in regulatory milestone Option exercise fee per Collaboration USD 15.0 million payments will be received if Juno’s investigational drugs Development Program (CDP) obtain regulatory approval. An additional USD 75 million Development milestone payments USD 42 million in commercial milestone payments per therapeutic area for each CDP will be received if any future products resulting from this Product approval and launch USD 75.0 million collaboration achieve certain sales levels. milestone payments per CDP Sales milestone payments per CDP USD 90 million Corporate partnerships create the possibility of much larger sources of financing and growth for a Philippine genomics facility. In contrast to fees for services, corporate partnership revenue provides financing beyond R&D

25 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines spending and gives rewards for achieving milestones that that healthcare programs have the potential for the will stimulate growth. Although a Philippine genomics greatest corporate partnership revenue over programs facility will likely not receive payments as large as in agriculture and fisheries. In order to reach this a biotechnology company with a unique proprietary conclusion, we evaluated the price per kilogram of technology, achieving one-tenth the corporate partnership products developed from agriculture, fisheries, and the revenue that Editas Medicine obtains will be significant. pharmaceutical industry. Table 6 displays the average price per kilogram for various products in agriculture, fisheries, and healthcare. The challenge for commodity Potential Corporate Partnership Programs for a items from agriculture and fisheries is their low price. Philippine Genomics Facility If the price per kilogram averages PHP 19.79 for palay We evaluated different programs and concluded and PHP 120.00 to 136.67 for skipjack tuna, agricultural and fisheries companies may find it difficult to justify Table 6. Price per kilogram for palay, skipjack tuna, milkfish, and funding for a program if the technology enhancements Humira (adalimumab). make the commodity have an unsellable price of PHP Product Price per kilogram (PHP/kg) 45 per kilogram for genetically-enhanced rice. On the Commodities other hand, long-term government funding into genomic Palay (rice) 19.79 biomarker-guided enhancements in certain traits by Skipjack tuna 120.00–136.67 conventional breeding – such as for drought resistance Milkfish 113.75–156.38 or insect resistance – is still a worthy investment likely Pharmaceutical drug to be funded by government agencies and philanthropic Humira (adalimumab) 22.5 billion organizations like the Bill and Melinda Gates Foundation. Sources: PSA (2019) and BFAR (2019); Humira price per kg calculated from 2017 sales and price per 40 mg dose In contrast to commodities, the retail price of the number

Figure 7. Potential corporate partnership deal structures for a genomics facility: A) exclusive partnership with a corporate partner; B) open access to genomics facility through a consortium of corporate partners; C) genomics facility spins off private entity, which partners exclusively with a corporate partner; D) consortium of corporate partnerships with multiple companies wherein one corporate partner may later claim exclusive rights to a specific area (hatched area).

26 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines one drug Humira is PHP 22.5 billion per kilogram (1600x more valuable than gold), making it one of the most precious materials on the planet. Based on Humira’s unit price, we estimate that only 270 kg was needed to provide the world’s annual supply in 2017. The huge value that pharmaceutical companies capture from developing and selling prescription medicines is the reason that pharmaceutical companies are willing to pay significant sums to companies like Editas Medicine for technologies that can create new drugs. Hence, the highest probability for a genomics facility to generate large revenue is through corporate partnerships for healthcare programs. Potential deal structures for a Philippine genomics facility are illustrated in Figure 7. Several legal restrictions pose challenges for a government genomics facility in the Philippines. For example, an exclusive partnership between Figure 8. Annual sales of three branded oncology drugs and the a pharmaceutical company and a genomics facility (Figure effect of patent expiration on the sales of Gleevec 7A) is not allowed in the Philippines because government (imatinib). Herceptin (trastuzumab) is an anti-HER2 institutes must offer equal access to all potential partners. monoclonal antibody indicated for HER2-positive breast This may pose problems with pharmaceutical companies cancer. Avastin (bevacizumab) is an anti-VEGF antibody that place value on exclusivity and patent rights to indicated for glioblastomas and ovarian cancers. Gleevec marketed products. However, a consortium between a (imatinib) is a small molecule BCR-ABL protein tyrosine kinase inhibitor indicated for Philadelphia chromosome- genomics facility with multiple partners is allowed (Figure positive CML. 7B). This leads to the possibility of a bioinformatics consortium where multiple partners have equal access to a bioinformatics database, followed by exclusive licensing timeline for drug development because the patents are rights to a specific therapeutic area (with licensing fees, filed at the lead identification stage, not after the drug is upfront payments, milestone payments, and royalties) proven in clinical trials. Shortening the developmental that an individual partner later decides that it wants to timeline for Herceptin, for example, and launching the pursue (Figure 7D). Numerous possibilities exist for drug one year earlier would generate another PHP 370 this type of deal structure e.g., territorial splits wherein billion before Herceptin's patent expires in 2019. the partner has a right to all of Europe but not to Asia, therapeutic splits based upon therapeutic area, specific We therefore examined areas that would attract lead compounds that result from the collaboration, etc. pharmaceutical companies to partner with a Philippine This type of deal structure and consortium was previously genomics facility. We intentionally focused on the clinical not uncommon between population genomics companies trials phase of the drug discovery value chain because it and a consortium of pharmaceutical companies wanting has a higher value to pharmaceutical companies and is access to bioinformatics databases. A genomics facility closer to the market. The bottleneck in drug discovery has could also spin out a private entity (Figure 7C). There are progressively moved up the value to chain – from target advantages to spinning off a private entity that is relieved identification and lead identification to clinical trials. The of government restrictions, including faster procurement low cost of conducting clinical trials in the Philippines is times for urgent equipment and supplies and the ability also an attraction. to exclusively partner with a corporation. One unexploited area that would attract pharmaceutical The reason that pharmaceutical companies value companies is patient recruitment for clinical trials through exclusivity is that the pharmaceutical industry has one oncology clinical genomics. Delays of over a year can be of the highest dependencies upon patents. Significantly, experienced in recruiting even a small, 25-patient Phase I patents set a time limit for the useful life of a branded drug clinical trial because recruitment relies upon participating before it is replaced by generics. Patents have a fixed life physicians to find patients satisfying a strict set of span of 20 years after the time of filing. Figure 8 illustrates criteria e.g., patients between a specific age range with how patent expiration dramatically reduced the sales of a particular disease that failed the first-line and second- the oncology drug Gleevec (imatinib) in 2016. Therefore, line therapy and that do not present with confounding in addition to marketed drugs, pharmaceutical companies unrelated health conditions. Recruitment is even more place a high value on technologies that can shorten the challenging for a 10,000-patient, multi-institutional Phase

27 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines

III cardiovascular clinical trial. Hence, recruitment for associate genomic variations and digital imaging data to oncology clinical trials is an intelligent focus area for disease (for a total of PHP 3.1 billion). a Philippine genomics facility because of the extensive number of biomarkers for new oncology investigational The UK Biobank consortium indicates that today, drugs and the lower number of patients required for pharmaceutical companies place a higher value on clinical trials. A genomics-based oncology clinical trial bioinformatics content than on DNA sequencing recruitment program can be combined with a tumor services. In support of this conviction is the personal biopsy biobank wherein tissue samples are genomically, genomics company 23andMe, which tests individuals’ proteomically, and histopathologically profiled and saliva samples for ancestry and health predictions analyzed before storage. In addition to a tumor tissue for only Php 5,000. However, the extensive data that biobank, computing processing is now powerful enough 23andMe collected matching DNA information with to perform digital histopathology and automated image voluntary health information created a bioinformatics analysis using artificial intelligence algorithms of database that was worth USD 300 million (PHP 15 tumor histopathology thin sections to classify tumors billion) to GlaxoSmithKline in 2018 for access to (Coudray et al. 2018). Surgical pathologists are the 23andMe’s database. Nebula Genomics, a personal gate keepers for treatment options for cancer patients genomics company using blockchain technology for since they are the ones that grade and stage tumor types. privacy, is offering free genomics services as part of Although major Philippine hospitals have automated its bioinformatics and corporate partnership business workflows for creating histopathology thin sections, the model. Facebook and Google are examples of companies interpretation by pathologists is still a very subjective and that offer free services yet generate billions of dollars in tedious procedure. Hence, the establishment of a digital revenue from access to their databases. pathology database by a genomics facility should promote Another potential area to explore is drug repositioning adoption by surgical pathologists. Coupled with a tumor or the repurposing of failed or approved drugs for tissue biobank that can be proactively and retroactively new indications. Celgene, for example, repositioned analyzed for molecular biomarkers and tied to patient thalidomide (and its analog Revlimid) – which was records, an anonymized informatics database can rapidly banned for use as an antiemetic for pregnant women match patients with specific tumors and biomarkers for – to become a multibillion-dollar drug for multiple recruitment into clinical trials for new investigational myeloma. Examples of approved drugs that have targeted oncology therapies. been repositioned for new indications include an Pharmaceutical and biotechnology companies place a high anti-smoking drug that was originally indicated for value on biobanks that are characterized by biomarkers depression, a multiple sclerosis drug that was originally and matched to patient histories. The UK Biobank is approved for psoriasis, and a drug for dry eyes that was a 500,000-patient, government-funded biobank that is originally used to prevent organ transplant rejection matched to the extensive database of patient histories (Table 7). Drug repositioning is an attractive area for a collected by the centralized government healthcare system genomics corporate partnership because investigational in the United Kingdom. The medical history of volunteers drugs can begin in late-stage Phase II or III clinical is also tracked throughout their lives. In 2018, the UK trials. The reason for this is that the drugs have already Biobank formed a consortium with six pharmaceutical been approved for safety in another indication. Since and biotechnology companies to fund the creation of finding new indications for repositioning of approved a genomic exon sequencing database of the biobank’s drugs can be accelerated by biomarker signature 500,000 volunteers that are matched to their medical and profiling and bioinformatic pathway analyses offered health records. In order to accelerate the DNA sequencing, by genomics facilities (Pushpakom et al. 2019), drug Regeneron Pharmaceuticals, Abbvie, AstraZeneca, Biogen, repositioning is a low-risk, high-return program Pfizer, and the RNA interference company Alnylam will that genomics facilities in the Philippines can offer each commit USD 10 million to the biobank program to pharmaceutical companies in conjunction with low-

Table 7. Examples of repositioned (repurposed) drugs. Zyban Tecfidera Restasis Procysbi Active ingredient Bupropion Dimethyl fumarate Cyclosporine Dimethyl fumarate Marketer GlaxoSmithKline Biogen Allergan Raptor Indication Smoking Multiple sclerosis Dry eyes Nephropathic cystinosis Previous indication Depression Psoriasis Organ transplant rejection prophylaxis Cystinosis

28 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines cost, lower-risk clinical trials. tumor biopsy biobank to create a bioinformatics database that will accelerate oncology clinical trials recruitment may be one way to capture value. Another possibility is the use of genomics-based technologies to identify new OUTLOOK AND CONCLUSIONS indications for repositioned drugs. Corporate partnerships can result in significant value capture for a genomics The establishment of a government-backed genomics facility through upfront payments, milestone payments, facility in the Philippines enables all Philippine institutes and royalties. Corporate partnerships also have the benefit to participate in high impact activities that benefit the of knowledge transfer and reduction to practice. Hence, Philippines. The precision of DNA-based applications partnering with a foreign pharmaceutical company should allows for unique and powerful solutions that are not be discouraged since they have the experience and specifically tailored for Philippine patients, Philippine skill sets at translating the discovery research from the crops, Philippine fisheries, Philippine livestock, and the genomics facility into developed applications. Philippine environment. The challenge is in sustaining a Philippine genomics facility long enough to realize its Philippine laws must be relaxed to allow government long-term benefits. research institutes to partner with for-profit companies the way it is encouraged in Europe and America. For Genomics, bioinformatics, and high-throughput example, the number one drug Humira was discovered by technologies provide a way to accelerate research discovery the companies BASF and Cambridge Antibody Technology that leads to new high impact applications. They are not the in partnership with the British government-funded Medical applications themselves. Hence, the Philippine government Research Council (MRC). The number one genomics must be patient and realize that the research discovery facility the world, The of MIT and Harvard, of new molecular biomarkers and genes associated with is a non-profit institute that licensed CRISPR gene editing a specific disease pathway leads to new and improved patents to Editas Medicine Inc. in exchange for Editas medicines for Filipinos, but that the average development Medicine stocks. Both the Broad Institute and Harvard are time from discovery to market is 10–17 years. Genomics entitled to USD 54 million (PHP 2.8 billion) in milestone will lead to the creation of stronger Philippine crops with payments from each licensed product resulting from greater yield, but the biomarkers and genes for drought- the collaboration. In another example, the University of or insect-resistant crops must first be characterized by California San Francisco (UCSF) – a government university genomics-based technologies. Moreover, once useful – entered into a drug discovery collaboration with the genes are identified in the laboratory, the genes for those Swiss pharmaceutical company Roche. UCSF receives traits must be bred back into elite lines that are optimized financial support from Roche and is entitled to further to grow in specific territories of the Philippines. This may funding in excess of USD 13 million plus royalties upon the take years and many generations of breeding. Monsanto achievement of developmental and commercial milestones. (now Bayer Crop Science), for example, will attempt to accelerate breeding by compressing as many generations Genomics in the Philippines is a government initiative into a single year by growing crops in the United States in similar to the so-called “war on cancer” in the United the summertime and then in the Southern hemisphere in the States or the initiative to combat AIDS in its early infancy wintertime, and then in Asia. The same applies to livestock. when the etiology of the disease was poorly understood. Genomics can lead to new diagnostic tests that can guide Both are basic research initiatives. When Nobel laureate policy on how to protect Philippine coral reefs and a major David Baltimore testified in the United States Congress source of food and jobs for the Philippines, but the basic when it was debating how much money was necessary to research in identifying stress-specific biomarkers of coral fund AIDS research to develop a cure, Professor Baltimore bleaching must first be accomplished. A challenge for a correctly pointed out that biological research is not an Philippine genomics facility is therefore a political one that engineering project like going to the Moon where you must survive potential impatience of the government, which can calculate an exact line-item budget. Rather, Professor tend to look for short-term solutions. A second challenge Baltimore pointed out that it is the nature of science not to is a business challenge to remain sustainable as fees for be able to predict which direction that hypothesis-driven services of rapidly commoditizing technologies cannot research will take you. Yet, despite the uncertainties of support growth to reach a critical mass. the necessary basic research required to understand the mechanism by which HIV causes AIDS, the result of the One possibility to reach a critical mass and sustainability government initiative has been the creation of new drugs is to partner with pharmaceutical and biotechnology that allow HIV-positive patients to lead normal lives. companies that see advantages in the Philippines to create high-value products. Clinical genomics revolved around Basic, non-targeted, curiosity-driven research has led to oncology, digital image analysis of histopathology, and a more profound breakthroughs that benefit society than

29 Special Issue on Genomics Young: Creating a Roadmap for Building a Sustainable Genomics Facility in the Philippines short-term applied research. For example, the discovery of Alexander Young developed genomics strategies for the structure of DNA or the discovery of CRISPR-based numerous venture capital firms and pharmaceutical, gene editing technologies would not have been permitted biotechnology, and agricultural companies in the past and if those researchers were blocked by accountants from may continue to do so in the future. deviating from their original grant and line-item budget to explore new areas, as was permitted and encouraged in Great Britain and the United States. Hence, Philippine government policymakers must allow high-impact genomics projects to ACKNOWLEDGMENTS succeed by allowing the country’s scientists and physicians We wish to acknowledge Cyrille Eliz C. Gregorio, M.Sc. to have time and freedom. Genomics facilities should also and Jemily M. Sales, M.Sc. for help in preparing the have tax-exempt status, considering the contributions that figures and tables. they will make to the country. A few comments must be made about the restriction of Philippine science by the Philippine procurement system for equipment and supplies. Genomics-based research REFERENCES programs are high-impact projects that compete with BISHOP JM, VARMUS HE. 2019. The Nobel Prize in other institutions in other countries. For the Philippines Physiology or Medicine 1989. Stockholm: Nobel to get international recognition, it is necessary to win Media AB. Retrieved from https://www.nobelprize. the international race to complete high-impact projects. org/prizes/medicine/1989/summary/ on 15 Mar 2019. However, the procurement system and bidding process have established a vendor ecosystem where it takes three [BFAR] Bureau of Fisheries and Aquatic Resources. months or more to make a purchase order and three months 1997. Philippine profile: Department of Agriculture or more for delivery of items that cost 2–3 times as much – Bureau of Fisheries and Aquatic Resources, as in other countries. When competitors in other countries Manila. Retrieved from https://www.bfar.da.gov.ph/ can place a purchase order in one day and receive the publications.jsp?id=29#post on 15 Mar 2019. shipment by the next day, the competition is already six [BFAR] Bureau of Fisheries and Aquatic Resources. months ahead by the time Philippine institutes receive 2019. Average weekly prices (per kilo) of fresh fish their instruments or supplies. commodities monitored in Luzon (for December 2018 Genomics research has already made substantial Region IV-B). Retrievd from https://www.bfar.da.gov. contributions to the world. Genomics research will ph/files/img/photos/Luzon.1.4.15.pdf contribute significantly to the Philippine population by BRUNO JF, SELIG ER. 2007. Regional decline of creating solutions that are tailored to the Philippines. coral cover in the Indo-Pacific: Timing, extent, and Near-term solutions will likely come from molecular subregional comparisons. PLOS One 2(8): 711. diagnostics that can predict and guide treatment options and therapeutic outcomes for patients, detect pathogens, CARPENTER KE, ABRAR M, AEBY G, ARONSON and find new ways to monitor Philippine biodiversity RB, BANKS S, BRUCKNER A, CHIRIBOGA A, and ecology. Longer-term solutions will come in the CORTÉS J, DELBEEK JC, DEVANTIER L, EDGAR way of new precision medicines, crops, and livestock GJ, EDWARDS AJ, FENNER D, GUZMÁN HM, that are optimized for the Philippines. Genomics HOEKSEMA BW, HODGSON G, JOHAN O, facilities make these high technologies available to the LICUANAN WY, LIVINGSTONE SR, LOVELL Philippine community at large so that the entire Philippine ER, MOORE JA, OBURA DO, OCHAVILLO D, community can collectively collaborate to use genomics POLIDORO BA, PRECHT WF, QUIBILAN MC, for a better Philippines. REBOTON C, RICHARDS ZT, ROGERS AD, SANCIANGCO J, SHEPPARD A, SHEPPARD C, SMITH J, STUART S, TURAK E, VERON JE, WALLACE C, WEIL E, WOOD E. 2008. One-third STATEMENT ON CONFLICT OF of reef-building corals face elevated extinction risk INTEREST from climate change and local impacts. Science 321: 560–563. CASKEY CT. 1997. Sequence to function in mammals. Second Annual Conference on Functional Genomics; IBC, San Diego, CA.

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