**4. IP outputs of synthetic biology and public concerns**

Deciphering the working of a cell, leave alone creating an artificial one, is far more than just listing its constituent parts, *e.g.*, listing its genes. We also need to know how the parts connect and operate together, *e.g.*, how genes and proteins interact to, say, form larger modules and circuits analogous to those in electronic systems. More sophisticated conceptual understand‐ ing is needed to advance synthetic biology towards rational construction and redesign of biological circuitry. In addition, development of new computer models, computational algorithms and experimental techniques are needed for exploring gene interactions. Already known techniques, such as chemical modification of proteins and splicing and rearrangement of genetic information in the DNA have matured to a level where they can be used to redesign basic molecular interactions and pathways of living cells. Further, the development of machines and methods for rapid synthesis of DNA with specified sequences has made it possible to build wholly synthetic, highly complex collections of genes and even to synthesize living organisms from the genome up. In fact, biology inspired templates for engineering nanostructures is emerging as a dominant research theme.

Notable contributions in synthetic biology include those from Dae-Kyun Ro, *et al*, Production of the antimalarial drug precursor artemisinic acid in engineered yeast, [Nature, 2006] in therapeutics; Marc Gitzinger, *et al*, Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin, [PNAS, 2009] in therapeutics; Shota Atsumi, *et al*, Non-fermentative pathways for synthesis of branched-chain higher alcohols as biofuels, [Nature, 2008] in fuels; Yoon Sung Nam, *et al*, Biologically template photocatalytic nanostructures for sustained light-driven water oxidation, [Nature Nanotech‐ nology, 2010] in solar energy; John E. Dueber, *et al*, Synthetic protein scaffolds provide modular control over metabolic flux, [Nature Biotechnology, 2009] in chemicals; Tae Seok Moon, *et al*, Use of modular, synthetic scaffolds for improved production of glucaric acid in engineered E. coli, [Metabolic Engineering, 2010] in chemicals; Michael B. Elowitz & Stanislas Leibler, A synthetic oscillatory network of transcriptional regulators, [Nature, 2000] in biological computing, programmability; Eileen Fung, *et al*, A synthetic gene-metabolic oscillator, [Nature, 2005] in biological computing, programmability; Marcel Tigges, *et al*, A tuneable synthetic mammalian oscillator, [Nature, 2009] in biological computing, programmability; Tai Danino, A synchronized quorum of genetic clocks, [Nature, 2010] in biological computing, programm‐ ability; Daniel G. Gibson, *et al*, Creation of a bacterial cell controlled by a chemically synthe‐ sized genome, [Science, 2010], in extending the principles of design and construction to whole organisms; Denis A. Malyshev, *et al*, A semi-synthetic organism with an expanded genetic alphabet, [Nature, 2014], in expanding the genetic code to incorporate unnatural nucleotides and base pairing; Cong, L., *et al*, Multiplex Genome Engineering Using CRISPR/Cas Systems, [Science, 2013], in gene editing.

Research efforts in synthetic biology are largely concentrated in the United States and to a substantially lesser degree in the European Union. Currently no country has the necessary framework for coordinating its research activities, fostering a community of researchers, and creating a forum for the establishment of goals, shared tools, and professional standards. Biological research, more than ever, needs to address ethical and safety concerns of society, especially with respect to synthetic biology if the research community is to gain public trust without raising Frankensteinian fears.

In general, perceived safety and investment risks involved in converting proof-of-concept products and processes developed in laboratories and making them market ready are very high and intimately related to the mode of IP dissemination, *e.g*., open source, patents, IP commons, and private law initiatives. The last is based on contractual agreements that are basically binding among those involved and not on third parties. The open source movement has generally restricted itself to basic research outputs that form the foundation on which subsequent applied research depends. As synthetic biology results move out of research labs and migrate to industry to be integrated into marketable products, altruistic open source initiatives and private profit motive collide. The potential for fierce litigation suddenly arises whose source is the patent system, which has the unenviable task of delicately balancing the need to encourage innovation through grants of limited period monopoly and protect public interest through minimal free-market encroachment.

#### **4.1. The bright side of IP outputs**

Patent laws of a country do not over-ride its other laws that might regulate the invention's use. Patent laws of a country may take into account moral, cultural, ethical, social, environmental, or scientific concerns of society. Patent rights may be exercised by the patentee, his heirs or assigns. When a patent expires, the related invention becomes the common heritage of

Limited period patent monopoly may provide an enormous first mover advantage to an entrepreneur, especially if it involves new technology that could lead to a natural monopoly.

Traditional medicine is the sum total of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention,

This knowledge, much of it undocumented and available only to small groups of people through oral transmission from generation to generation, predates molecular biology by centuries and hence belongs to prior art (public domain). Its importance to synthetic biology is that such knowledge may provide promising directions of research in the hunt for exotic

Deciphering the working of a cell, leave alone creating an artificial one, is far more than just listing its constituent parts, *e.g.*, listing its genes. We also need to know how the parts connect and operate together, *e.g.*, how genes and proteins interact to, say, form larger modules and circuits analogous to those in electronic systems. More sophisticated conceptual understand‐ ing is needed to advance synthetic biology towards rational construction and redesign of biological circuitry. In addition, development of new computer models, computational algorithms and experimental techniques are needed for exploring gene interactions. Already known techniques, such as chemical modification of proteins and splicing and rearrangement of genetic information in the DNA have matured to a level where they can be used to redesign basic molecular interactions and pathways of living cells. Further, the development of machines and methods for rapid synthesis of DNA with specified sequences has made it possible to build wholly synthetic, highly complex collections of genes and even to synthesize living organisms from the genome up. In fact, biology inspired templates for engineering

Notable contributions in synthetic biology include those from Dae-Kyun Ro, *et al*, Production of the antimalarial drug precursor artemisinic acid in engineered yeast, [Nature, 2006] in therapeutics; Marc Gitzinger, *et al*, Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin, [PNAS, 2009] in therapeutics;

The World Health Organisation (WHO) defines traditional medicine as [30]:

diagnosis, improvement or treatment of physical and mental illness.

**4. IP outputs of synthetic biology and public concerns**

nanostructures is emerging as a dominant research theme.

mankind.

204 Biotechnology

genes.

**3.5. Traditional knowledge**

Due to genetic engineering, modern biotechnology has progressed well beyond simply using natural strains, classic breeding, and strain selection to produce a variety of chemical products. Artemisinin, a critical ingredient in malaria drugs is now pro‐ duced from yeast altered through synthetic biology. Rennet, a key processing aid in cheese making, since the 1990s has been made by a microbe altered with insertion of a single bovine gene and is in wide use in the U.S. Algal oil is produced by geneti‐ cally modifying algae which is now used in making laundry detergent. Synthetic biology techniques are now used to coax bacteria, fungi and other organisms into producing substances they would not otherwise produce. Some of the micro-organisms synthetic biologists create to make ingredients like orange and grapefruit flavourings have passed the muster of the Environmental Protection Agency of the U.S. while the U.S. Food and Drug Administration says the ingredients they produce are "generally recognized as safe". Some companies also produce food-grade vanillin, resveratrol and citrus flavourings from yeast and other microorganisms via synthetic biology. Yet enough misgivings in public perception exist that companies shy away from admitting that some of their products are created or mediated by artificial organisms made possible by synthetic biology [31]. Nevertheless, synthetic biology continues to tackle far more ambitious goals. Here are some examples.


#### **4.2. The dark side of IP outputs**

duced from yeast altered through synthetic biology. Rennet, a key processing aid in cheese making, since the 1990s has been made by a microbe altered with insertion of a single bovine gene and is in wide use in the U.S. Algal oil is produced by geneti‐ cally modifying algae which is now used in making laundry detergent. Synthetic biology techniques are now used to coax bacteria, fungi and other organisms into producing substances they would not otherwise produce. Some of the micro-organisms synthetic biologists create to make ingredients like orange and grapefruit flavourings have passed the muster of the Environmental Protection Agency of the U.S. while the U.S. Food and Drug Administration says the ingredients they produce are "generally recognized as safe". Some companies also produce food-grade vanillin, resveratrol and citrus flavourings from yeast and other microorganisms via synthetic biology. Yet enough misgivings in public perception exist that companies shy away from admitting that some of their products are created or mediated by artificial organisms made possible by synthetic biology [31]. Nevertheless, synthetic biology continues to tackle far more

**1.** *Three-person IVF*. The Human Fertilization and Embryology Authority in the U.K. that regulates the use of human eggs, sperm, and embryos in treatment and research has assessed two types of in vitro fertilisation (IVF) methods: one that involves removing parental nuclei from a fertilized egg and placing them into a donor embryo from a second woman, and another that moves the nucleus from the mother's egg into a donor egg, which then can be fertilized. The aim is to help women with mitochondrial diseases have healthy babies. The report [32] noted that three-person IVF is expected to be ready for use in preventing the birth of children with mitochondrial disease through assisted conception in about two years. Its use on humans in the U.K. will need Parliamentary approval. **2.** *Next generation sequencing*. Fourteen year old Joshua lay in a coma for weeks, his brain swelling with fluid due to an unknown cause. With parental approval, doctors ran a test with an experimental new technology that searched the child's cerebrospinal fluid for pieces of DNA that might belong to the pathogen causing his encephalitis. They were able to pinpoint the cause within 48 hours. The child had been infected with an obscure species of bacteria, which the doctors eradicated within days [33]. The technology although years away from clinical use has raised hopes of powerful diagnostic tools for presently

**3.** *Exome sequencing*. In June 2014, researchers in the *Finding of Rare Disease Genes* (FORGE*)* project reported analysing 264 rare disorders using exome sequencing and identifying the

**4.** *Whole-genome sequencing*. A recent paper in Nature [35] has suggested that whole-genome sequencing can diagnose severe intellectual disability in newborns even when standard tests don't. Based on data on 50 patients with severe intellectual disability and their unaffected parents, the genome-wide analysis found 84 novel sequence variations and 8 novel structural variations associated with the disability. Previous gene screens in the same patients had failed to identify disease markers. The results led to a diagnosis of 42

ambitious goals. Here are some examples.

206 Biotechnology

undiagnosable diseases becoming available in the future.

causal mutations to 146 of them and identifying 67 novel genes [34].

percent of patients studied. Can a synthetic biology remedy be far behind?

New technologies come with unknown risks of using and not using it! They have their share of scary stories and apprehensions. Construction of artificial life that goes well beyond traditional recombinant DNA technology, is both ambitious and ominous. But then modern civilization is the result of past risk taking. With older and mature technologies we gradually found ways of muting their dark side by enacting legislation and creating regulatory bodies.

While possible socio-economic benefits from synthetic biology are enormous, so is the possibility of its misuse. The concerns range from bioethical and environmental worries to bioterrorism, say, by malicious release of genetically engineered viruses targeted at specific population groups. The main concern is the creation and growth of bio-weapons. They can be created surreptitiously, cheaply, on a mass scale, and released in a variety of inexpensive ways into the environment using a variety of delayed triggering mechanisms that would camouflage their presence. Bio-weapons make the lethality of atomic and nuclear weapons passé.

A panel of life sciences experts in 2003 noted [40]:


A decade later, these concerns have become more pronounced. The threat spectrum is diverse and elusive and already impossible to comprehensively defend against. The pace, breadth, and volume of the evolving scientific base in synthetic biology and its easy public accessibility makes the controlled development of bio-weapons a hopeless task.

## **4.3. The regulatory side of IP outputs**

Synthetic biology ingredients are rapidly entering consumer products and food [31]. The legitimate concern of various advocacy groups is that synthetic biology is so new that there are as yet no regulations in place for the creation, use, and disposal of new synthetic organisms or even credible risk assessment methods before such organisms are released in the environ‐ ment [41, 42]. The fear is that premature, wider, large-scale industrial use of synthetic biology ingredients is likely to cause serious harm to biodiversity and farmers. The fact remains that scientists cannot predict, at this nascent stage of synthetic biology, what new forms of life or attempts to 'reprogram' existing organisms, such as yeast and algae, would do to the envi‐ ronment and human life, given that they can now generate millions of new, untested organisms on a mass production scale. The possible effects range from beneficial, benign, to ecological and economic disaster. The core ecological concern is that artificial organisms breed, repro‐ duce, and once released into the environment cannot be recalled. Hence the fear of unintended consequences. Of course, as synthetic biology matures, many equitable solutions are also likely to emerge.

In this 'good-bad' debate, the real concern is the regulation of artificially created living organisms rather than the non-living chemical products (bio-fuels, pharmaceuticals, oils, etc.) they produce. For the latter, reasonable regulatory mechanisms exist and they are continuously evolving. Chemistry is much better understood than the biochemistry of life. Therefore, the demand, as is sometimes made, for labelling ingredients as having come from synthetic biology processes in products has no scientific basis. The chemical properties of an ingredient are independent of the process used in making them.

The regulatory aspect of such synthetic biology products as genetically engineered microbes, plants and animals, promises to be a nightmare. Concerns related to environmental, health, and food safety require specialized regulating agencies. R&D advances in synthetic biology have been so rapid and novel that existing regulatory agencies are either unable to cope or find themselves without the authority to review. The sheer variety and increasing complexity of artificial life, many of which can be generated within a short span, makes their risk assess‐ ment a great challenge. Not only will the regulators need additional funding to meet increased workload and expertise requirements, but also the legal authority to carry out certain tasks not included in current laws. See, *e.g.*, [16]. Most countries currently lack human, financial, and scientific resources to set up effective regulatory agencies or even frame regulatory policies.

Another major concern is the accidental release of artificial organisms in the environment. In some cases, researchers can design organisms with built-in safety features. For example, by designing organisms that can survive and breed only in an artificially created environment, such as by controlling the chemical sources of energy they have access to or by the reassignment of the stop codon. It was recently discovered that in the standard genetic code the stop codon can undergo recoding in nature. Reassignment of the stop codon has been observed in bacteriophages and bacteria indicating that bacteriophages can infect hosts with a different genetic code. This can lead to phage-host antagonism based on code differences. Its implication in synthetic biology is that the stop codon reassignment may be used as a means to engineer organisms to prevent the exchange of genetic information between engineered and naturally occurring species.

Clearly, synthetic biology requires new methods of risk assessment because it involves exotic biological systems based on an alternative biochemical structure, *e.g.*, genetic code based on novel types of nucleotides, or an enlarged number of base pairs. There is also the risk of synthetic biology skills diffusing into wrong hands (*e.g.*, Do-it-yourself biology, amateurs, and bio-hackers) with time as these skills begin to percolate down the education system.

#### **4.4. The societal side of IP outputs**

A panel of life sciences experts in 2003 noted [40]:

known to man."

208 Biotechnology

to emerge.

advanced biological weapons."

**4.3. The regulatory side of IP outputs**

independent of the process used in making them.

**•** "The effects of some of these engineered biological agents could be worse than any disease

**•** "The genomic revolution is pushing biotechnology into an explosive growth phase. … [T]he resulting wave front of knowledge will evolve rapidly and be so broad, complex, and widely available to the public that traditional intelligence means for monitoring WMD [weapons of mass destruction] development could prove inadequate to deal with the threat from these

A decade later, these concerns have become more pronounced. The threat spectrum is diverse and elusive and already impossible to comprehensively defend against. The pace, breadth, and volume of the evolving scientific base in synthetic biology and its easy public accessibility

Synthetic biology ingredients are rapidly entering consumer products and food [31]. The legitimate concern of various advocacy groups is that synthetic biology is so new that there are as yet no regulations in place for the creation, use, and disposal of new synthetic organisms or even credible risk assessment methods before such organisms are released in the environ‐ ment [41, 42]. The fear is that premature, wider, large-scale industrial use of synthetic biology ingredients is likely to cause serious harm to biodiversity and farmers. The fact remains that scientists cannot predict, at this nascent stage of synthetic biology, what new forms of life or attempts to 'reprogram' existing organisms, such as yeast and algae, would do to the envi‐ ronment and human life, given that they can now generate millions of new, untested organisms on a mass production scale. The possible effects range from beneficial, benign, to ecological and economic disaster. The core ecological concern is that artificial organisms breed, repro‐ duce, and once released into the environment cannot be recalled. Hence the fear of unintended consequences. Of course, as synthetic biology matures, many equitable solutions are also likely

In this 'good-bad' debate, the real concern is the regulation of artificially created living organisms rather than the non-living chemical products (bio-fuels, pharmaceuticals, oils, etc.) they produce. For the latter, reasonable regulatory mechanisms exist and they are continuously evolving. Chemistry is much better understood than the biochemistry of life. Therefore, the demand, as is sometimes made, for labelling ingredients as having come from synthetic biology processes in products has no scientific basis. The chemical properties of an ingredient are

The regulatory aspect of such synthetic biology products as genetically engineered microbes, plants and animals, promises to be a nightmare. Concerns related to environmental, health, and food safety require specialized regulating agencies. R&D advances in synthetic biology have been so rapid and novel that existing regulatory agencies are either unable to cope or find themselves without the authority to review. The sheer variety and increasing complexity of artificial life, many of which can be generated within a short span, makes their risk assess‐

makes the controlled development of bio-weapons a hopeless task.

Since artificially created biological systems will often be expected to interact with natural biological systems, including human societies, there are moral and ethical concerns and the need to develop a rational public–science interface to address those concerns [44]. In particular, what should be the relationship between humans and artificially created living organisms and the moral and legal status of the products, *e.g.*, transgenic humans. Indeed, how would we define human life? What would be the legal status of artificial humans, especially if illegally created? What if they formed their own societies, rules of governance and rules of interaction with natural humans? What if there were to occur a sudden spurt of diversification of the human species, engineered or accidental? Could it lead to the collapse of human society as we know it today and the extinction of natural humans?

Precision editing of DNA will eventually enable us to alter not just individual organisms but also ecosystems. It would then be possible to wipe out diseases like malaria by altering Anopheles mosquitoes, which have evolved resistance to anti-malarial drugs and insecticides (a vaccine against malaria has been elusive), by modifying their genome, disabling or hinder‐ ing their reproductive cycle or building up resistance to parasites through highly heritable genes, and then releasing them throughout the population. However, the accessible nature of the technology, such a "gene drive" could also be used irresponsibly and raise the risks of accidental or even intentional harmful effects [45]. Given the delicate ecological balance needed for human survival, how is responsible behaviour to be integrated with the patent system?

Historically, pioneering technologies have created intense patentability debates [46, 47] that range from conceptual to political. For example, IPR opponents in the past had argued agriculture was not an industry, patents on pharmaceuticals would be unethical, biotechnol‐ ogy is about trying to play God, software and business methods are non-technical, etc. In the 1970s, concerns surfaced about recombinant DNA technology that innocuous microbes could be engineered into human pathogens resistant to then known antibiotics, or enable them to produce toxins, or transform them into cancer causing agents [47]. Fears have since abated. Recombinant DNA technology now dominates research in biology. In synthetic biology, the fears are more in terms of our ability to regulate research and industrial activities so that these activities are carried out safely [16] and the human species preserved.

## **4.5. The IPR side of IP outputs**

In societies that abhor monopoly rights and favour level playing fields of competition, even limited period monopoly creates social tension. Thomas Jefferson (1743–1826), the third President of the United States (1801–1809), the principal author of the Declaration of Inde‐ pendence (1776), a well-known scientist of his time, the initiator of the first U.S. patent system in 1790, and the author of the 1793 Patent Act, had this to say in 1813 in a letter to Isaac McPherson [48]:

Considering the exclusive right to invention as given not of natural right, but for the benefit of society, I know well the difficulty of drawing a line between the things which are worth to the public the embarrassment of an exclusive patent, and those which are not.

The demarcation debate between openness and limited period monopoly may never end. In synthetic biology this debate is complex because it involves the assimilation of a new technol‐ ogy by society and of inventions that were never anticipated to become part of the patent system. Indeed, some of these future inventions may well be bio-robots and bio-computers with the DNA serving as programmable memory. It would require tremendous legislative efforts to equitably deal with such live inventions. However, one expects that bio-weapons, like atomic weapons, would be kept outside the patent system.
