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Current research in biotechnology: Exploring the biotech forefront

2019, Current Research in Biotechnology

Biotechnology is an evolving research field that covers a broad range of topics. Here we aimed to evaluate the latest research literature, to identify prominent research themes, major contributors in terms of institutions, countries/re-gions, and journals. The Web of Science Core Collection online database was searched to retrieve biotechnology articles published since 2017. In total, 12,351 publications were identified and analyzed. Over 8500 institutions contributed to these biotechnology publications, with the top 5 most productive ones scattered over France, China, the United States of America, Spain, and Brazil. Over 140 countries/regions contributed to the biotechnology research literature, led by the United States of America, China, Germany, Brazil, and India. Journal of Bioscience and Bioengineer-ing was the most productive journal in terms of number of publications. Metabolic engineering was among the most prevalent biotechnology study themes, and Escherichia coli and Saccharomyces cerevisiae were frequently used in biotechnology investigations, including the biosynthesis of useful biomolecules, such as myo-inositol (vitamin B8), mono-terpenes, adipic acid, astaxanthin, and ethanol. Nanoparticles and nanotechnology were identified too as emerging biotechnology research themes of great significance. Biotechnology continues to evolve and will remain a major driver of societal innovation and development.

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Scientists worldwide are continuing to discover unique properties of every day materials at the submicrometer scale. This size domain is better known as nanometer domain and technology concerned with this is known as nanotechnology that involves working with particles at nano level. One of the most important emerging fields of science in this centur y is Nanotechnology. It deals with designing, construction, investigation and utilization of systems at the nanoscale. The interface between nanotechnology and biotechnology is nanobiotechnology, which exploits nanotechnology and biotechnology to analyse a nd create nanobiosystems to meet a wide variety of challenges and develops a wide range of applications. Biotechnology gives us a way to understand biological system and to utilize our knowledge for industrial manufacturing. Nanotechnology has great potent ial and by the help of its application it can enhance the quality of life through in various fields like agriculture and the food system. Around the world, it has become the future of any nation. Important tools used in nanotechnology and application of nanobiotechnology in agriculture sector will be discussed in this review.

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Open Access

The future is bright, the future is biotechnology

* E-mail: [email protected]

Affiliation Public Library of Science, San Francisco, California, United States of America and Cambridge, United Kingdom

• Richard Hodge, 
• on behalf of the PLOS Biology staff editors

Published: April 28, 2023

• https://doi.org/10.1371/journal.pbio.3002135
• Reader Comments

As PLOS Biology celebrates its 20 th anniversary, our April issue focuses on biotechnology with articles covering different aspects of the field, from genome editing to synthetic biology. With them, we emphasize our interest in expanding our presence in biotechnology research.

Citation: Hodge R, on behalf of the PLOS Biology staff editors (2023) The future is bright, the future is biotechnology. PLoS Biol 21(4): e3002135. https://doi.org/10.1371/journal.pbio.3002135

Copyright: © 2023 Hodge, on behalf of the PLOS Biology staff editors. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

The PLOS Biology Staff Editors are Ines Alvarez-Garcia, Joanna Clarke, RichardHodge, Paula Jauregui, Nonia Pariente, Roland Roberts, and Lucas Smith.

This article is part of the PLOS Biology 20th Anniversary Collection.

Biotechnology is a revolutionary branch of science at the forefront of research and innovation that has advanced rapidly in recent years. It is a broad discipline, in which organisms or biological processes are exploited to develop new technologies that have the potential to transform the way we live and work, as well as to boost sustainability and industrial productivity. The new tools and products being generated have a wide range of applications across various sectors, including medicine, agriculture, energy, manufacturing and food.

PLOS Biology has traditionally published research reporting significant advances across a wide range of biological disciplines. However, our scope must continue to evolve as biology increasingly becomes more and more applied, generating technologies with potentially game-changing therapeutic and environmental impact. To that end, we recently published a collection of magazine articles focused on ideas for green biotechnologies that could have an important role in a sustainable future [ 1 ], including how to harness microbial photosynthesis to directly generate electricity [ 2 ] and using microbes to develop carbon “sinks” in the mining industry [ 3 ]. Moreover, throughout this anniversary year we are publishing Perspective articles that take stock of the past 20 years of biological research in a specific field and look forward to what is to come in the next 20 years [ 4 ]; in this issue, these Perspectives focus on different aspects of the broad biotechnology field—synthetic biology [ 5 ] and the use of lipid nanoparticles (LNPs) for the delivery of therapeutics [ 6 ].

One fast moving area within biotechnology is gene editing therapy, which involves the alteration of DNA to treat or prevent disease using techniques such as CRISPR-Cas9 and base editors that enable precise genetic modifications to be made. This approach shows great promise for treating a variety of genetic diseases. Excitingly, promising phase I results of the first in vivo genome editing clinical trial to treat several liver-related diseases were reported at the recent Keystone Symposium on Precision Genome Engineering. This issue of PLOS Biology includes an Essay from Porto and Komor that focuses on the clinical applications of base editor technology [ 7 ], which could enable chronic diseases to be treated with a ‘one-and-done’ therapy, and a Perspective from Hamilton and colleagues that outlines the advances in the development of LNPs for the delivery of nucleic acid-based therapeutics [ 6 ]. LNPs are commonly used as vehicles for the delivery of such therapeutics because they have a low immunogenicity and can be manufactured at scale. However, expanding the toolbox of delivery platforms for these novel therapeutics will be critical to realise their full clinical potential.

Synthetic biology is also a rapidly growing area, whereby artificial or existing biological systems are designed to produce products or enhance cellular function. By using CRISPR to edit genes involved in metabolic pathways, researchers can create organisms that produce valuable compounds such as biofuels, drugs, and industrial chemicals. In their Perspective, Kitano and colleagues take stock of the technological advances that have propelled the “design-build-test-learn” cycle methodology forward in synthetic biology, as well as focusing on how machine-learning approaches can remove the bottlenecks in these pipelines [ 5 ].

While the potential of these technologies is vast, there are also concerns about their safety and ethical implications. Gene editing, in particular, raises ethical concerns, as it could be used to create so-called “designer babies” with specific traits or to enhance physical or mental capabilities. There are also concerns about the unintended consequences of gene editing, such as off-target effects that could cause unintended harm. These technologies can be improved by better understanding the interplay between editing tools and DNA repair pathways, and it will be essential for scientists and policymakers to be cautious and work together to establish guidelines and regulations for their use, as outlined at the recent International Summit on Human Genome Editing .

Basic research has also benefitted from biotechnological developments. For instance, methodological developments in super-resolution microscopy offer researchers the ability to image cells at exquisite detail and answer previously inaccessible research questions. Sequencing technologies such as Nanopore sequencers are revolutionising the ability to sequence long DNA/RNA reads in real time and in the field. Great strides have also been made in the development of analysis software for structural biology purposes, such as sub-tomogram averaging for cryo-EM [ 8 ]. The rate of scientific discovery is now at an unprecedented level in this age of big data as a result of these huge technological leaps.

The past few years has also seen the launch of AI tools such as ChatGPT. While these tools are increasingly being used to help write students homework or to improve the text of scientific papers, generative AI tools hold the potential to transform research and development in the biotechnology industry. The recently developed language model ProGen can generate and then predict function in protein sequences [ 9 ], and these models can also be used to find therapeutically relevant compounds for drug discovery. Protein structure prediction programs, such as AlphaFold [ 10 ] and RosettaFold, have revolutionized structural biology and can be used for a myriad of purposes. We have recently published several papers that have utilized AlphaFold models to develop methods that determine the structural context of post-translational modifications [ 11 ] and predict autophagy-related motifs in proteins [ 12 ].

The future of biotechnology is clearly very promising and we look forward to being part of the dissemination of these important new developments. Open access science sits at the core of our mission and the publication of these novel technologies in PLOS Biology can help their widespread adoption and ensure global access. As we look forward during this year of celebration, we are excited that biotechnology research will continue to grow and become a central part of the journal. The future is bright and the future is very much biotechnology.

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An Introduction to Biotechnology

Varsha gupta.

5 Institute of Biosciences and Biotechnology, Chhatrapati Shahu Ji Maharaj University, Kanpur, UP India

Manjistha Sengupta

6 George Washington University, Washington DC, USA

Jaya Prakash

7 Orthopaedics Unit, Community Health Centre, Kanpur, UP India

Baishnab Charan Tripathy

8 School of Life sciences, Jawaharlal Nehru University, New Delhi, India

Biotechnology is multidisciplinary field which has major impact on our lives. The technology is known since years which involves working with cells or cell-derived molecules for various applications. It has wide range of uses and is termed “technology of hope” which impact human health, well being of other life forms and our environment. It has revolutionized diagnostics and therapeutics; however, the major challenges to the human beings have been threats posed by deadly virus infections as avian flu, Chikungunya, Ebola, Influenza A, SARS, West Nile, and the latest Zika virus. Personalized medicine is increasingly recognized in healthcare system. In this chapter, the readers would understand the applications of biotechnology in human health care system. It has also impacted the environment which is loaded by toxic compounds due to human industrialization and urbanization. Bioremediation process utilizes use of natural or recombinant organisms for the cleanup of environmental toxic pollutants. The development of insect and pest resistant crops and herbicide tolerant crops has greatly reduced the environmental load of toxic insecticides and pesticides. The increase in crop productivity for solving world food and feed problem is addressed in agricultural biotechnology. The technological advancements have focused on development of alternate, renewable, and sustainable energy sources for production of biofuels. Marine biotechnology explores the products which can be obtained from aquatic organisms. As with every research area, the field of biotechnology is associated with many ethical issues and unseen fears. These are important in defining laws governing the feasibility and approval for the conduct of particular research.

Introduction

The term “ biotechnology” was coined by a Hungarian engineer Karl Ereky, in 1919, to refer to the science and methods that permit products to be produced from raw materials with the aid of living organisms. Biotechnology is a diverse field which involves either working with living cells or using molecules derived from them for applications oriented toward human welfare using varied types of tools and technologies. It is an amalgamation of biological science with engineering whereby living organisms or cells or parts are used for production of products and services. The main subfields of biotechnology are medical (red) biotechnology, agricultural (green) biotechnology, industrial (white) biotechnology, marine (blue) biotechnology, food biotechnology, and environmental biotechnology (Fig. 1.1 .). In this chapter the readers will understand the potential applications of biotechnology in several fields like production of medicines; diagnostics; therapeutics like monoclonal antibodies, stem cells, and gene therapy; agricultural biotechnology; pollution control ( bioremediation); industrial and marine biotechnology; and biomaterials, as well as the ethical and safety issues associated with some of the products.

Major applications of biotechnology in different areas and some of their important products

The biotechnology came into being centuries ago when plants and animals began to be selectively bred and microorganisms were used to make beer, wine, cheese, and bread. However, the field gradually evolved, and presently it is the use or manipulation of living organisms to produce beneficiary substances which may have medical, agricultural, and/or industrial utilization. Conventional biotechnology is referred to as the technique that makes use of living organism for specific purposes as bread/cheese making, whereas modern biotechnology deals with the technique that makes use of cellular molecules like DNA, monoclonal antibodies, biologics, etc. Before we go into technical advances of DNA and thus recombinant DNA technology, let us have the basic understanding about DNA and its function.

The foundation of biotechnology was laid down after the discovery of structure of DNA in the early 1950s. The hereditary material is deoxyribonucleic acid (DNA) which contains all the information that dictates each and every step of an individual’s life. The DNA consists of deoxyribose sugar, phosphate, and four nitrogenous bases (adenine, guanine, cytosine, and thymine). The base and sugar collectively form nucleoside, while base, sugar, and phosphate form nucleotide (Fig. 1.2 ). These are arranged in particular orientation on DNA called order or sequence and contain information to express them in the form of protein. DNA has double helical structure, with two strands being complimentary and antiparallel to each other, in which A on one strand base pairs with T and G base pairs with C with two and three bonds, respectively. DNA is the long but compact molecule which is nicely packaged in our nucleus. The DNA is capable of making more copies like itself with the information present in it, as order or sequence of bases. This is called DNA replication. When the cell divides into two, the DNA also replicates and divides equally into two. The process of DNA replication is shown in Fig. 1.3 , highlighting important steps.

The double helical structure of DNA where both strands are running in opposite direction. Elongation of the chain occurs due to formation of phosphodiester bond between phosphate at 5′ and hydroxyl group of sugar at 3′ of the adjacent sugar of the nucleotide in 5–3′ direction. The sugar is attached to the base. Bases are of four kinds: adenine ( A ), guanine ( G ) (purines), thymine ( T ), and cytosine ( C ) (pyrimidines). Adenine base pairs with two hydrogen bonds with thymine on the opposite antiparallel strand and guanine base pairs with three hydrogen bonds with cytosine present on the opposite antiparallel strand

The process of DNA replication. The DNA is densely packed and packaged in the chromosomes. The process requires the action of several factors and enzymes. DNA helicase unwinds the double helix. Topoisomerase relaxes DNA from its super coiled nature. Single-strand binding proteins bind to single-stranded open DNA and prevent its reannealing and maintains strand separation. DNA polymerase is an enzyme which builds a new complimentary DNA strand and has proofreading activity. DNA clamp is a protein which prevents dissociation of DNA polymerase. Primase provides a short RNA sequence for DNA polymerase to begin synthesis. DNA ligase reanneals and joins the Okazaki fragments of the lagging strand. DNA duplication follows semiconservative replication, where each strand serves as template which leads to the production of two complimentary strands. In the newly formed DNA, one strand is old and the other one is new (semiconservative replication). DNA polymerase can extend existing short DNA or RNA strand which is paired to template strand and is called primer. Primer is required as DNA polymerase cannot start the synthesis directly. DNA polymerase is capable of proofreading, that is, correction of wrongly incorporated nucleotide. One strand is replicated continuously with single primer, and it is called as leading strand. Other strand is discontinuous and requires the addition of several primers. The extension is done in the form of short fragments called as Okazaki fragments. The gaps are sealed by DNA ligase. Replication always occurs in 5′–3′ direction

DNA contains whole information for the working of the cell. The part of the DNA which has information to dictate the biosynthesis of a polypeptide is called a “gene.” The arrangement or order of nucleotides determines the kind of proteins which we produce. Each gene is responsible for coding a functional polypeptide. The genes have the information to make a complimentary copy of mRNA. The information of DNA which makes RNA in turn helps cells to incorporate amino acids according to arrangement of letters for making many kinds of proteins. These letters are transcribed into mRNA in the form of triplet codon, where each codon specifies one particular amino acid. The polypeptide is thus made by adding respective amino acids according to the instructions present on RNA. Therefore, the arrangement of four bases (adenine, guanine, cytosine, and thymine) dictates the information to add any of the 20 amino acids to make all the proteins in all the living organisms. Few genes need to be expressed continuously, as their products are required by the cell, and these are known as “constitutive genes.” They are responsible for basic housekeeping functions of the cells. However, depending upon the physiological demand and cell’s requirement at a particular time, some genes are active and some are inactive, that is, they do not code for any protein. The information contained in the DNA is used to make mRNA in the process of “ transcription” (factors shown in Table 1.1 ). The information of mRNA is used in the process of “ translation” for production of protein. Transcription occurs in the nucleus and translation in the cytoplasm of the cell. In translation several initiation factors help in the assembly of mRNA with 40S ribosome and prevent binding of both ribosomal subunits; they also associate with cap and poly(A) tail. Several elongation factors play an important role in chain elongation. Though each cell of the body has the same genetic makeup, but each is specialized to perform unique functions, the activation and expression of genes is different in each cell. Thus, one type of cells can express some of its genes at one time and may not express the same genes some other time. This is called “temporal regulation” of the gene. In the body different cells express different genes and thus different proteins. For example, liver cell and lymphocyte, would express different genes. This is known as spatial regulation of the gene. Therefore, in the cells of the body, the activation of genes is under spatial regulation (cells present at different locations and different organs produce different proteins) and temporal regulation (same cells produce different proteins at different times). The proteins are formed by the information contained in the DNA and perform a variety of cellular functions. The proteins may be structural (responsible for cell shape and size), or they may be functional like enzymes, signaling intermediates, regulatory proteins, and defense system proteins. However, any kind of genetic defect results in defective protein or alters protein folding which can compromise the functioning of the body and is responsible for the diseases. Figure 1.4 shows the outline of the process of transcription and translation with important steps.

Factors involved in transcription process

It shows the process of transcription and translation. Transcription occurs in the nucleus and requires the usage of three polymerase enzymes. RNApol I for rRNA, pol II for mRNA, and pol III for both rRNA and tRNA. RNApol II initiates the process by associating itself with seven transcription factors, TFIIA, TFIIB, TFIID, TFIIE, TFIIH, and TFIIJ. After the synthesis, preRNA transcript undergoes processing to form mRNA by removal of introns by splicing and polyadenylation and capping. Protein synthesis is initiated by formation of ribosome and initiator tRNA complex to initiation codon (AUG) of mRNA and involves 11 factors. Chain elongation occurs after sequential addition of amino acids by formation of peptide bonds. Then polypeptide can fold or conjugate itself to other biomolecules and may undergo posttranslational modifications as glycosylation or phosphorylation to perform its biological functions

The biotechnological tools are employed toward modification of the gene for gain of function or loss of function of the protein. The technique of removing, adding, or modifying genes in the genome or chromosomes of an organism to bring about the changes in the protein information is called genetic engineering or recombinant DNA technology (Fig. 1.5 ). DNA recombination made possible the sequencing of the human genome and laid the foundation for the nascent fields of bioinformatics, nanomedicine, and individualized therapy. Multicellular organisms like cows, goats, sheep, rats, corn, potato, and tobacco plants have been genetically engineered to produce substances medically useful to humans. Genetic engineering has revolutionized medicine, enabling mass production of safe, pure, more effective versions of biochemicals that the human body produces naturally [ 20 – 22 ].

The process of recombinant DNA technology. The gene of interest from human nucleus is isolated and cloned in a plasmid vector. The gene is ligated with the help of DNA ligase. The vector is transformed into a bacterial host. After appropriate selections, the gene is amplified when bacteria multiply or the gene can be sequenced or the gene can be expressed to produce protein

The technological advancements have resulted in (1) many biopharmaceuticals and vaccines, (2) new and specific ways to diagnose, (3) increasing the productivity and introduction of quality traits in agricultural crops, (4) the ways to tackle the pollutants efficiently for sustainable environmental practices, (5) helped the forensic experts by DNA fingerprinting and profiling, (6) fermentation technology for production of industrially important products. The list is very long with tremendous advancements and products which have boosted the economy of biotechnology sector worldwide [ 16 ]. The biotechnology industry and the products are regulated by various government organizations such as the US Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), and the US Department of Agriculture (USDA).

Medical Biotechnology

This fieldof biotechnology has many applications and is involved in production of recombinant pharmaceuticals, tissue engineering products, regenerative medicines such as stem cell and gene therapy, and many more biotechnology products for better human life (Fig. 1.6 ). Biotechnological tools produce purified bio-therapeutic agents on industrial scales. These include both novel agents and agents formerly available only in small quantities. Crude vaccines were used in antiquity in China, India, and Persia. For example, vaccination with scabs that contained the smallpox virus was a practice in the East for centuries. In 1798 English country doctor Edward Jenner demonstrated that inoculation with pus from sores due to infection by a related cowpox virus could prevent smallpox far less dangerously. It marked the beginning of vaccination. Humans have been benefited incalculably from the implementation of vaccination programs.

Various applications of medical biotechnology

Tremendous progress has been made since the early recombinant DNA technology (RDT) experiments from which the lively—and highly profitable—biotechnology industry emerged. RDT has fomented multiple revolutions in medicine. Safe and improved drugs, accelerated drug discovery, better diagnostic and quick methods for detecting an infection either active or latent, development of new and safe vaccines, and completely novel classes of therapeutics and other medical applications are added feathers in its cap. The technology has revolutionized understanding of diseases as diverse as cystic fibrosis and cancer. Pharmaceutical biotechnology being one of the important sectors involves using animals or hybrids of tumor cells or leukocytes or cells ( prokaryotic, mammalian) to produce safer, more efficacious, and cost-effective versions of conventionally produced biopharmaceuticals. The launch of the new biopharmaceutical or drug requires screening and development. Mice were widely used as research animals for screening. However, in the wake of animal protection, animal cell culture offers accurate and inexpensive source of cells for drug screening and efficacy testing. Pharmaceutical biotechnology’s greatest potential lies in gene therapy and stem cell-based therapy. The underlying cause of defect of many inherited diseases is now located and characterized. Gene therapy is the insertion of the functional gene in place of defective gene into cells to prevent, control, or cure disease. It also involves addition of genes for pro-drug or cytokines to eliminate or suppress the growth of the tumors in cancer treatment.

But the progress so far is viewed by many scientists as only a beginning. They believe that, in the not-so-distant future, the refinement of “targeted therapies” should dramatically improve drug safety and efficacy. The development of predictive technologies may lead to a new era in disease prevention, particularly in some of the world’s rapidly developing economies. Yet the risks cannot be ignored as new developments and discoveries pose new questions, particularly in areas as gene therapy, the ethics of stem cell research, and the misuse of genomic information.

Many bio-therapeutic agents in clinical use are biotech pharmaceuticals. Insulin was among the earliest recombinant drugs. Canadian physiologists Frederick Banting and Charles Best discovered and isolated insulin in 1921. In that time many patients diagnosed with diabetes died within a few years. In the mid-1960s, several groups reported synthesizing the hormone.

The first “bioengineered” drug, a recombinant form of human insulin, was approved by the US Food and Drug Administration (FDA) in 1982. Until then, insulin was obtained from a limited supply of beef or pork pancreas tissue. By inserting the human gene for insulininto bacteria, scientists were able to achieve lifesaving insulinproduction in large quantities. In the near future, patients with diabetes may be able to inhale insulin, eliminating the need for injections. Inhaled insulinproducts like Exubera® were approved by the USFDA; however, it was pulled out and other products like Technosphere® insulin (Afrezza®) are under investigation. They may provide relief from prandial insulin. Afrezza consists of a pre-meal insulinpowder loaded into a cartridge for oral inhalation.

Technosphere technology: The technology allows administration of therapeutics through pulmonary route which otherwise were required to be given as injections. These formulations have broad spectrum of physicochemical characteristics and are prepared with a diverse assortment of drugs with protein or small molecule which may be hydrobhobic or hydrophilic or anionic or cationic in nature. The technology can have its applicability not only through pulmonary route but also for other routes of administration including local lung delivery.

The first recombinant vaccine, approved in 1986, was produced by cloning a gene fragment from the hepatitis B virus into yeast (Merck’s Recombivax HB). The fragment was translated by the yeast’s genetic machinery into an antigenic protein. This was present on the surface of the virus that stimulates the immune response. This avoided the need to extract the antigen from the serum of people infected with hepatitis B.

The Food and Drug administration (FDA) approved more biotech drugs in 1997 than in the previous several years combined. The FDA has approved many recombinant drugs for human health conditions. These include AIDS, anemia, cancers (Kaposi’s sarcoma, leukemia, and colorectal, kidney, and ovarian cancers), certain circulatory problems, certain hereditary disorders (cystic fibrosis, familial hypercholesterolemia, Gaucher’s disease, hemophilia A, severe combined immunodeficiency disease, and Turner’s syndrome), diabetic foot ulcers, diphtheria, genital warts, hepatitis B, hepatitis C, human growth hormone deficiency, and multiple sclerosis. Today there are more than 100 recombinant drugs and vaccines. Because of their efficiency, safety, and relatively low cost, molecular diagnostic tests and recombinant vaccines may have particular relevance for combating long-standing diseases of developing countries, including leishmaniasis (a tropical infection causing fever and lesions) and malaria.

Stem cell research is very promising and holds tremendous potential to treat neurodegenerative disorders, spinal cord injuries, and other conditions related to organ or tissue loss.

DNA analysis is another powerful technique which compares DNA pattern [ 14 ] after performing RFLP and probing it by minisatellite repeat sequence between two or more individuals. Its modification, DNA profiling (process of matching the DNA profiles for STS markers in two or more individuals; see chapter 18), which utilizes multilocus PCR analysis of DNA of suspect and victims, is very powerful and is useful in criminal investigation, paternity disputes, and so many other legal issues. The analysis is very useful in criminal investigations and involves evaluation of DNA from samples of the hair, body fluids, or skin at a crime scene and comparison of these with those obtained from the suspects.

Improved Diagnostic and Therapeutic Capabilities

The sequencing of the human genome in 2003, has given scientists an incredibly rich “parts list” with which to better understand why and how disease happens. It has given added power to gene expression profiling, a method of monitoring expression of thousands of genes simultaneously on a glass slide called a microarray. This technique can predict the aggressiveness of cancer.

The development of monoclonal antibodies in 1975 led to a medical revolution. The body normally produces a wide range of antibodies—the immune system proteins—that defend our body and eliminate microorganisms and other foreign invaders. By fusing antibody-producing cells with myeloma cells, scientists were able to generate antibodies that would, like “magic bullets,” bind with specific targets including unique markers, called antigenic determinants ( epitopes), on the surfaces of inflammatory cells. When tagged with radioisotopes or other contrast agents, monoclonal antibodies can help in detecting the location of cancer cells, thereby improving the precision of surgery and radiation therapy and showing—within 48 h—whether a tumor is responding to chemotherapy.

The polymerase chain reaction, a method for amplifying tiny bits of DNA first described in the mid-1980s, has been crucial to the development of blood tests that can quickly determine exposure to the human immunodeficiency virus (HIV). Genetic testing currently is available for many rare monogenic disorders, such as hemophilia, Duchenne muscular dystrophy, sickle cell anemia, thalassemia, etc.

Another rapidly developing field is proteomics, which deals with analysis and identification of proteins. The analysis is done by two-dimensional gel electrophoresis of the sample and then performing mass spectrometric analysis for each individual protein. The technique may be helpful in detecting the disease-associated protein in the biological sample. They may indicate early signs of disease, even before symptoms appear. One such marker is C-reactive protein, an indicator of inflammatory changes in blood vessel walls that presage atherosclerosis.

Nanomedicine is a rapidly moving field. Scientists are developing a wide variety of nanoparticles and nanodevices, scarcely a millionth of an inch in diameter, to improve detection of cancer, boost immune responses, repair damaged tissue, and thwart atherosclerosis. The FDA has approved a paclitaxel albumin-stabilized nanoparticle formulation (Abraxane® for injectable suspension, made by Abraxis BioScience) for the treatment of metastatic adenocarcinoma of the pancreas. Nanoparticles are being explored in heart patients in the USA as a way to keep their heart arteries open following angioplasty.

Therapeutic proteins are those, which can replace the patients naturally occurring proteins, when levels of the natural proteins are low or absent due to the disease. High-throughput screening, conducted with sophisticated robotic and computer technologies, enables scientists to test tens of thousands of small molecules in a single day for their ability to bind to or modulate the activity of a “target,” such as a receptor for a neurotransmitter in the brain. The goal is to improve the speed and accuracy of therapeutic protein or potential drug discovery while lowering the cost and improving the safety of pharmaceuticals that make it to market.

Many of the molecules utilized for detection also have therapeutic potential too, for example, monoclonal antibodies. The monoclonal antibodies are approved for the treatment of many diseases as cancer, multiple sclerosis, and rheumatoid arthritis. They are currently being tested in patients as potential treatments for asthma, Crohn’s disease, and muscular dystrophy. As the antibodies may be efficiently targeted against a particular cell surface marker, thus they are used to deliver a lethal dose of toxic drug to cancer cells, avoiding collateral damage to nearby normal tissues.

Agricultural Biotechnology

The manhas made tremendous progress in crop improvement in terms of yield; still the ultimate production of crop is less than their full genetic potential. There are many reasons like environmental stresses (weather condition as rain, cold, frost), diseases, pests, and many other factors which reduce the ultimate desired yield affecting crop productivity. The efforts are going on to design crops which may be grown irrespective of their season or can be grown in frost or drought conditions for maximum utilization of land, which would ultimately affect crop productivity [ 24 ]. Agricultural biotechnology aims to introduce sustainable agriculturalpractices with best yield potential and minimal adverse effects on environment (Fig. 1.7 ). For example, combating pests was a major challenge. Thus, the gene from bacterium , the Bt gene, that functions as insect-resistant gene when inserted into crop plants like cotton, corn, and soybean helps prevent the invasion of pathogen, and the tool is called . This management is helpful in reducing usage of potentially dangerous pesticides on the crop. Not only the minimal or low usage of pesticides is beneficial for the crop but also the load of the polluting pesticides on environment is greatly reduced [ 24 ].

Various applications of agricultural biotechnology

Resistance to Infectious Agents Through Genetic Engineering

• The gene comes from the soil bacterium .
• The gene produces crystal proteins called Cry proteins. More than 100 different variants of the Bt toxins have been identified which have different specificity to target insect lepidoptera. For eg., CryIa for butterflies and CRYIII for beetles.
• These Cry proteins are toxic to larvae of insects like tobacco budworm, armyworm, and beetles.
• The Cry proteins exist as an inactive protoxins.
• These are converted into active toxin in alkaline pH of the gut upon solubilization when ingested by the insect.
• After the toxin is activated, it binds to the surface of epithelial cells of midgut and creates pores causing swelling and lysis of cells leading to the death of the insect (larva).
• The genes (cry genes) encoding this protein are isolated from the bacterium and incorporated into several crop plants like cotton, tomato, corn, rice, and soybean.

The proteins encoded by the following cry genes control the pest given against them:

• Cry I Ac and cry II Ab control cotton bollworms.
• Cry I Ab controls corn borer.
• Cry III Ab controls Colorado potato beetle.
• Cry III Bb controls corn rootworm.
• A nematode infects tobacco plants and reduces their yield.
• The specific genes (in the form of cDNA) from the parasite are introduced into the plant using -mediated transformation.
• The genes are introduced in such a way that both sense/coding RNA and antisense RNA (complimentary to the sense/coding RNA) are produced.
• Since these two RNAs are complementary, they form a double-stranded RNA (ds RNA).
• This neutralizes the specific RNA of the nematode, by a process called RNA – interference.
• As a result, the parasite cannot multiply in the transgenic host, and the transgenic plantis protected from the pest.

These resistant crops result in reduced application of pesticides. The yield is high without the pathogen infestations and insecticides. This also helps to reduce load of these toxic chemicals in the environment.

The transformation techniques and their applications are being utilized to develop rice, cassava, and tomato, free of viral diseases by “International Laboratory for Tropical Agricultural Biotechnology” (ILTAB). ILTAB in 1995 reported the first transfer of a resistance gene from a wild-type species of rice to a susceptible cultivated rice variety. The transferred gene expressed and imparted resistance to crop-destroying bacterium Xanthomonas oryzae . The resistant gene was transferred into susceptible rice varieties that are cultivated on more than 24 million hectares around the world [ 6 ].

The recombinant DNA technology reduces the time between the identification of a particular gene to its application for betterment of crops by skipping the labor-intensive and time-consuming conventional breeding [ 3 ]. For example, the alteration of known gene in plant for the improvement of yield or tolerance to adverse environmental conditions or resistance to insect in one generation and its inheritance to further generations. Plant cell and tissue culture techniques are one of the applications where virus-free plants can be grown and multiplied irrespective of their season on large scale (micropropogation), raising haploids, or embryo rescue. It also opens an opportunity to cross two manipulated varieties or two incompatible varieties (protoplast culture) for obtaining best variety for cultivation.

With the help of technology, new, improved, and safe agricultural products may emerge which would be helpful for maintaining contamination-free environment. Biotechnology has the potential to produce:

• High crop yields [ 4 ]
• Crops are engineered to have desirable nutrients and better taste (e.g., tomatoes and other edible crops with increased levels of vitamin C, vitamin E, and/or beta-carotene protect against the risk of some prevalent chronic diseases and rice with increased iron levels protects against anemia)
• Insect- and disease-resistant plants
• Genetic modification avoids nonselective changes
• Longer shelf life of fruits and vegetables

The potential of biotechnology may contribute to increasing agricultural, food, and feed production, protecting the environment, mitigating pollution, sustaining agricultural practices, and improving human and animal health. Some agricultural crops as corn and marine organisms can be potential alternative for biofuel production. The by-products of the process may be processed to produce other chemical feedstocks for various products. It is estimated that the world’s chemical and fuel demand could be supplied by such renewable resources in the first half of the next century [ 5 ].

Food Biotechnology

Food biotechnology is an emerging field, which can increase the production of food, improving its nutritional content and improving the taste of the food. The food is safe and beneficial as it needs fewer pesticides and insecticides. The technology aims to produce foods which have more flavors, contain more vitamins and minerals, and absorb less fat when cooked. Food biotechnology may remove allergens and toxic components from foods, for their better utility [ 6 , 7 ].

Environmental Biotechnology

Environmental biotechnology grossly deals with maintenanceof environment, which is pollution-free, the water is contamination-free, and the atmosphere is free of toxic gases. Thus, it deals with waste treatment, monitoring of environmental changes, and pollution prevention. Bioremediation in which utilization of higher living organisms (plants: phytoremediation) or certain microbial species for decontamination or conversion of harmful products is done is the main application of environmental biotechnology. The enzyme bioreactors are also being developed which would pretreat some industrial and food waste components and allow their removal through the sewage system rather than through solid waste disposal mechanisms. The production of biofuel from waste can solve the fuel crisis (biogas). Microbes may be engineered to produce enzymes required for conversion of plant and vegetable materials into building blocks for biodegradable plastics. In some cases, the by-products of the pollution-fighting microorganisms are themselves useful. For example, methane can be derived from a form of bacteria that degrades sulfur liquor, a waste product of paper manufacturing. This methane thus obtained is used as a fuel or in other industrial processes. Insect- and pest-resistant crops have reduced the use and environmental load of insecticides and pesticides. Insect-protected crops allow for less potential exposure of farmers and groundwater to chemical residues while providing farmers with season-long control.

Industrial Biotechnology

The utilizationof biotechnological tools (bioprocessing) for the manufacturing of biotechnology-derived products (fuels, plastics, enzymes, chemicals, and many more compounds) on industrial scale is industrial biotechnology. The aim is to develop newer industrial manufacturing processes and products, which are economical and better than preexisting ones with minimal environmental impact. In industrial biotechnology, (1) microorganisms are being explored for producing material goods like fermentation products as cheese; (2) biorefineries where oils, sugars, and biomass may be converted into biofuels, bioplastics, and biopolymers; (3) and value-added chemicals from biomass. The utilization of modern techniques can improve the efficiency and reduces the environmental impacts of industrial processes like textile, paper, pulp, and chemical manufacturing. For example, development and usage of biocatalysts, such as enzymes, to synthesize chemicals and development of antibiotics and better tasting liquors and their usage in food industry have provided safe and effective processing for sustainable productions. Biotechnological tools in the textile industry are utilized for the finishing of fabrics and garments. Biotechnology also produces spider silk and biotech-derived cotton that is warmer and stronger and has improved dye uptake and retention, enhanced absorbency, and wrinkle and shrink resistance.

Biofuels may be derived from photosynthetic organisms, which capture solar energy, transform it in other products like carbohydrates and oils, and store them. Different plants can be used for fuel production:

• Bioethanol can be obtained from sugar (as sugarcane or sugar beet) or starch (like corn or maize). These are fermented to produce ethanol, a liquid fuel commonly used for transportation.
• Biodiesel can be obtained from natural oils from plants like oil palm, soybean, or algae. They can be burned directly in a diesel engine or a furnace, or blended with petroleum, to produce fuels such as biodiesel.
• Wood and its by-products can be converted into liquid biofuels, such as methanol or ethanol, or into wood gas. Wood can also be burned as solid fuel, like the irewood.

In these kinds of biological reaction, there are many renewable chemicals of economic importance coproduced as side streams of bioenergy and biofuels as levulinic acid, itaconic acid, and sorbitol. These have tremendous economic potential and their fruitful usage would depend upon the collaboration for research and development between the government and the private sector.

Enzyme Production

The enzymeshave big commercial and industrial significance. They have wide applications in food industry, leather industry, pharmaceuticals, chemicals, detergents, and research. In detergents the alkaline protease, subtilisin (from Bacillus subtilis ), was used by Novo Industries, Denmark. The production of enzymes is an important industrial application with world market of approximately 5 billion dollars. The enzymes can be obtained from animals, plants, or microorganisms. The production from microorganisms is preferred as they are easy to maintain in culture with simple media requirements and easy scale-up. The important enzymes for the industrial applications are in food industry, human application, and research. A few animal enzymes are also important as a group of proteolytic enzymes, for example, plasminogen activators, which act on inactive plasminogen and activate it to plasmin, which destroys fibrin network of blood clot. Some of the plasminogen activators are urokinase and tissue plasminogen activators (t-PA). Urokinase (from urine) is difficult to obtain in ample quantity; thus, t-PA is obtained from cells grown in culture medium. Streptokinase (bacterial enzyme) is also a plasminogen activator but is nonspecific and immunogenic.

Enzyme engineering is also being tried where modifications of specific amino acid residue are done for improving the enzyme properties. One of the enzymes chymosin (rennin) coagulates milk for cheese manufacturing.

The enzymes can be produced by culturing cells, growing them with appropriate substrates in culture conditions. After optimum time the enzymes may be obtained by cell disruption (enzymatic/freeze–thaw/osmotic shock) followed by preparative steps (centrifugation, filtration), purification, and analysis. The product is then packaged and ultimately launched in the market.

After their production, they can be immobilized on large range of materials (agar, cellulose, porous glass, or porous alumina) for subsequent reuse. Some of the important industrial enzymes are α-amylase (used for starch hydrolysis), amyloglucosidase (dextrin hydrolysis), β-galactosidase (lactose hydrolysis), aminoacylase (hydrolysis of acylated L-amino acids), glucose oxidase (oxidation of glucose), and luciferase (bioluminescence). Some of the medically important enzymes are urokinase and t-PA for blood clot removal and L-asparaginase for removal of L-asparagine essential for tumor growth and thus used for cancer chemotherapy in leukemia.

Exploring Algae for Production of Biofuels

The energyrequirement of present population is increasing and gradually fossil fuels are rapidly depleting. Thus, renewable energy sources like solar energy and wind-, hydro-, and biomass-based energy are being explored worldwide. One of the feedstocks may be microalgae, which are fast-growing, photosynthetic organisms requiring carbon dioxide, some nutrients, and water for its growth. They produce large amount of lipids and carbohydrates, which can be processed into different biofuels and commercially important coproducts. The production of biofuels using algal biomass is advantageous as they (1) can grow throughout the year and thus their productivity is higher than other oil seed crops, (2) have high tolerance to high carbon dioxide content, (3) utilize less water, (4) do not require herbicides or pesticides with high growth potential (waste water can be utilized for algal cultivation), (5) can sustain harsh atmospheric conditions, and (6) do not interfere with productivity of conventional crops as they do not require agricultural land. The production of various biofuels from algae is schematically represented in Fig. 1.8 .

Different biofuel productions by using microalgae. The algae use sunlight, CO2, water, and some nutrients

Algae can serve as potential source for biofuel production; however, biomass production is low. The production has certain limitations, as cultivation cost is high with requirement of high energy [ 1 ].

Marine or Aquatic Biotechnology

Marine or aquatic biotechnology also referred to as “blue biotechnology” deals with exploring and utilizing the marine resources of the world. Aquatic or marine life has been intriguing and a source of livelihood for many since years. As major part of earth is acquired by water, thus nearly 75–80 % types of life forms exist in oceans and aquatic systems. It studies the wide diversity found in the structure and physiology of marine organisms. They are unique in their own ways and lack their equivalent on land. These organisms have been explored and utilized for numerous applications as searching new treatment for cancer or exploring other marine resources, because of which the field is gradually gaining momentum and economic opportunities [ 19 ]. The global economic benefits are estimated to be very high. The field aims to:

• Fulfill the increasing food supply needs
• Identify and isolate important compounds which may benefit health of humans
• Manipulate the existing traits in sea animals for their improvement
• Protect marine ecosystem and gain knowledge about the geochemical processes occurring in oceans

Some of the major applications are discussed:

• Aquaculture: Aquaculture refers to the growth of aquatic organisms in culture condition for commercial purposes. These animals may be shellfish, finfish, and many others. Mariculture refers to the cultivation of marine animals. Their main applications are in food, food ingredients, pharmaceuticals, and fuels, the products are in high demand, and various industries are in aquaculture business, for example, crawfish farming (Louisiana), catfish industry (Alabama and Mississippi Delta), and trout farming (Idaho and West Virginia).
• Transgenic species of salmon with growth hormone gene has accelerated growth of salmons.
• Molt-inhibiting (MIH) from blue crabs leads to soft-shelled crab.
• : Anovel protein antifreeze protein (AFP) was identified. AFPs were isolated from Northern cod (bottom-dwelling fish) living at the Eastern Canada coast and teleosts living in extremely cold weather of Antarctica. AFPs have been isolated from Osmerus mordax (smelt), Clupea harengus (herring), Pleuronectes americanus (winter flounder), and many others. Due to antifreeze properties (lowering the minimal freezing temperature by 2–3 °C), the gene has potential for raising plants which are cold tolerant (e.g., tomatoes).
• Medicinal applications : For osteoporosis, salmon calcitonin (calcitonin is thyroid hormone promoting calcium uptake and bone calcification) with 20 times higher bioactivity is available as injection and nasal spray.
• Hydroxyapatite ( HA ): Obtained from coral reefs and is an important component of bone and cartilage matrix. Its implants are prepared by Interpore Internationals which may be used for filling gaps in fractured bones.

Many anti-inflammatory, analgesic, anticancerous compounds have been identified from sea organisms which can have tremendous potential for human health.

Tetrodotoxin (TTX) is the most toxic poison (10,000 times more lethal than cyanide) produced by Japanese pufferfish or blowfish ( Fugu rubripes ). TTX is being used to study and understand its effect on sodium channels which can help guide the development of drugs with anesthetic and analgesic properties.

Other Products

• Taq polymerase from Thermus aquaticus which is used in PCR reactions and obtained from hot spring Archaea.
• Collagenase (protease) obtained from Vibrio is used in tissue engineering and culturing.

Transgenic Animals and Plants

In the early1980s, inserting DNA from humans into mice and other animals became possible. The animals and plants which have foreign gene in each of their cells are referred to as transgenic organisms and the inserted gene as transgene. Expression of human genes in these transgenic animals can be useful in studies, as models for the development of diabetes, atherosclerosis, and Alzheimer’s disease. They also can generate large quantities of potentially therapeutic human proteins. Transgenic plants also offer many economic, safe, and practical solutions for production of variety of biopharmaceuticals. The plants have been engineered to produce many blood products (human serum albumin, cytokines), human growth hormone, recombinant antibodies, and subunitvaccines.

The usage of transgenic plants for the production of recombinant pharmaceuticals might open new avenues in biotechnology. As plants can be grown inexpensively with minimal complicated requirements, thus they may have tremendous therapeutic potential. The plants have been engineered to produce more nutrients or better shelf life. The transgenic plants have been created which have genes for insect resistance (Bt cotton, soybean, corn). Now billion acres of land is used for cultivation of genetically engineered crops of cotton, corn, and soybean as they have higher yield and are pest resistant. However, due to social, ethical, and biosafety issues, they have received acceptance as well as rejections at many places and health and environment-related concerns in many parts of the world [ 8 ].

Response to Antibiotic Resistance

Antibiotics areone of the broadly used therapeutic molecules produced by certain classes of microorganisms (bacteria and fungi) which can be used in diverse clinical situations to eliminate bacteria, improve symptoms, and prevent number of infections. Antibiotics have various other applications apart from clinical aspects. They can be used for the treatment of tumors and treatment of meat, in cattles and livestocks, in basic biotechnological work. However, their effectiveness is a matter of concern as bacteria which are continuously exposed to certain antibiotics might become resistant to it due to accumulation of mutations. These days antibiotic-resistant bacteria have increased and some of them have developed multiple drug resistance. Thus, it has become very difficult to initiate therapy in diseases like tuberculosis and leprosy. Biotechnology is solving the urgent and growing problem of antibiotic resistance. With the help of bioinformatics—powerful computer programs capable of analyzing billions of bits of genomicsequence data—scientists are cracking the genetic codes of bacteria and discovering “weak spots” vulnerable to attack by compounds identified via high-throughput screening. This kind of work led in 2000 to the approval of Zyvox (linezolid), an antibiotic to reach the market in 35 years.

Lytic bacteriophage viruses that infect and kill bacteria may be another way to counter resistance. First used to treat infection in the 1920s, “phage therapy” was largely eclipsed by the development of antibiotics. However, researchers in the former Soviet Republic of Georgia reported that a biodegradable polymer impregnated with bacteriophages and the antibiotic Cipro successfully healed wounds infected with a drug-resistant bacterium.

After exposure of strontium-90, three Georgian lumberjacks from village Lia had systemic effects, and two of them developed severe local radiation injuries which subsequently became infected with Staphylococcus aureus . Upon hospitalization, the patients were treated with various medications, including antibiotics and topical ointments; however, wound healing was only moderately successful, and their S. aureus infection could not be eliminated. Approximately 1 month after hospitalization, treatment with PhagoBioDerm (a wound-healing preparation consisting of a biodegradable polymer impregnated with ciprofloxacin and bacteriophages) was initiated. Purulent drainage stopped within 2–7 days. Clinical improvement was associated with rapid (7 days) elimination of the etiologic agent, and a strain of S. aureus responsible for infection was resistant to many antibiotics (including ciprofloxacin) but was susceptible to the bacteriophages contained in the PhagoBioDerm preparation [ 11 ].

The Challenges for the Technology

Gene therapy.

Some biotechapproaches to better health have proven to be more challenging than others. An example is gene transfer, where the defective gene is replaced with a normally functioning one. The normal gene is delivered to target tissues in most cases by virus that is genetically altered to render it harmless. The first ex vivo gene transfer experiment, conducted in 1990 at the National Institutes of Health (NIH), on Ashanti DeSilva who was suffering from severe combined immunodeficiency (SCID) helped boost her immune response and successfully corrected an enzyme deficiency. However, treatment was required every few months. However, 9 years later, a major setback occurred in gene therapy trial after the death of 18-year-old Jesse Gelsinger suffering from ornithine transcarbamylase (OTC) deficiency due to intense inflammatory responses followed by gene therapy treatment. There were some positive experiences and some setbacks from gene therapy trials leading to stricter safety requirements in clinical trials.

Designer Babies

The fancyterm designer baby was invented by media. Many people in society prefer embryos with better traits, intellect, and intelligence. They want to select embryo post germline engineering. This technique is still in infancy but is capable of creating lot of differences in the society thus requires appropriate guidelines.

Genetically Modified Food

Genetically modifiedcrops harboring genes for insect resistance were grown on billion of acres of land. These crops became very popular due to high yield and pest resistance. However, some of the pests gradually developed resistance for a few of these transgenic crops posing resistant pest threat. The other technologies as “traitor” and “terminator” technologies pose serious risk on crop biodiversity and would impart negative characters in the crop (they were not released due to public outcry).

Pharmacogenomics

Scientists do not believe they will find a single gene for every disease. As a result, they are studyingrelationships between genes and probing populations for variations in the genetic code, called single nucleotide polymorphisms, or SNPs, that may increase one’s risk for a particular disease or determine one’s response to a given medication. This powerful ability to assign risk and response to genetic variations is fueling the movement toward “individualized medicine.” The goal is prevention, earlier diagnosis, and more effective therapy by prescribing interventions that match patients’ particular genetic characteristics.

Tissue Engineering

Tissue engineering is one of the emerging fields with tremendous potential to supply replacement tissue and organ option for many diseases. Lot is achieved, lot more need to be achieved.

Ethical Issues

The pursuit of cutting-edge research “brings us closer to our ultimate goal of eliminating disability and disease through the best care which modern medicine can provide.” Understanding of the genetics of heart disease and cancer will aid the development of screening tools and interventions that can help prevent the spread of these devastating disorders into the world’s most rapidly developing economies.

Biotechnology is a neutral tool; nevertheless, its capabilities raise troubling ethical questions. Should prospective parents be allowed to “engineer” the physical characteristics of their embryos? Should science tinker with the human germ line, or would that alter in profound and irrevocable ways what it means to be human?

More immediately, shouldn’t researchers apply biotechnology—if they can—to eliminate health disparities among racial and ethnic groups? While genetic variation is one of many factors contributing to differences in health outcome (others include environment, socioeconomic status, health-care access, stress, and behavior), the growing ability to mine DNA databases from diverse populations should enable scientists to parse the roles these and other factors play.

Biotechnology along with supportive health-care infrastructure can solve complicated health problems. Accessibility to the new screening tests, vaccines, and medications and cultural, economic, and political barriers to change must be overcome. Research must include more people from disadvantaged groups, which will require overcoming long-held concerns, some of them have had about medical science.

Biotechnology has been a significant force which has improved the quality of lives and has incalculably benefitted human beings. However, technology does have prospects of doing harm also due to unanticipated consequences. Each technology is subjected to ethical assessment and requires a different ethical approach. Obviously the changes are necessary as technology can have major impact on the world; thus, a righteous approach should be followed. There is uncertainty in predicting consequences, as this powerful technology has potential to manipulate humans themselves. Ethical concerns are even more important as the future of humanity can change which require careful attention and consideration. Therefore, wisdom is required to articulate our responsibilities toward environment, animals, nature, and ourselves for the coming future generations. We need to differentiate what is important technologically rather that what technology can do. For an imperative question, that is, whether this can be achieved, the research must answer “Why should it be achieved”? Who would it benefit?

Issues Related to Safety

• As the new GM crops are entering the market, the issue regarding their consumption, whether they are safe, without any risk, is one of the important concerns [ 2 ]. Though the results related to safety and usage are well reported (as compared to conventional crops), unknown fear from these products makes them non acceptable at many places [ 20 ].
• As insect- and pest-resistant varieties are being prepared and used as Bt genes in corn and cotton crops, there exists a risk of development of resistance insect population. Another important factor is that these resistant crops may harm other species like birds and butterfly.
• The development of more weeds may occur as cross-pollination might result in production of weeds with herbicide resistance which would be difficult to control.
• The gene transfers might cross the natural species boundary and affect biological diversity.
• The judgment of their usage would depend upon the clear understanding of risks associated with safety of these products in determining the impact of these on environment, other crops, and other animal species.

Future of the Technology

With the understanding of science, we should understand that genetic transfers have been occurring in animals and plant systems; thus, the risk of the biotechnology-derived products is similar as conventional crops [ 12 ].

The biotechnology products would be acceptable to many if they are beneficial and safe. People are willing to buy crops free of pesticides and insecticides. Nowadays people are also accepting crops grown without the usage of chemical fertilizers or pesticides, which are high in nutritive values.

The labeling of the product is also an ethical issue as some believe that labeling any product as biotechnology product might be taken by consumer as warning signs; however, others believe that labeling should be done as consumer has every right to know what he is consuming [ 9 ]. The products may be acceptable if consumers can accept the food derived from biotechnology weighing all pros and cons and, if the price is right, has more nutritive values, is good in taste, and is safe to consume [ 10 ].

Biotechnology is at the crossroads in terms of fears and thus public acceptance [ 15 ]. Surprisingly the therapeutic products are all accepted and find major place in biopharmaceutical industry, but food crops are still facing problems in worldwide acceptance. The future of the world food supply depends upon how well scientists, government, and the food industry are able to communicate with consumers about the benefits and safety of the technology [ 13 , 16 ]. Several major initiatives are under way to strengthen the regulatory process and to communicate more effectively with consumers by conducting educational programs [ 18 , 23 ].

Chapter End Summary

• The advantages of biotechnology are so broad that it is finding its place in virtually every industry. It has applications in areas as diverse as pharmaceuticals, diagnostics, textiles, aquaculture, forestry, chemicals, household products, environmental cleanup, food processing, and forensics to name a few.
• Biotechnology is enabling these industries to make new or better products, often with greater speed, efficiency, and flexibility.
• With the applications of recombinant DNA technology, more safer and therapeutic drugs are produced. These recombinant products do not elicit unwanted immunological response which is observed when the product is obtained from other live or dead sources. Many of these therapeutics are approved for human usage, and many of them are in the phase of development.
• Immunological and DNA-based techniques like PCR (polymerase chain reaction) are used for early diagnosis of disorders. PCR and NAAT with microarray can be utilized for the diagnosis of many diseases, and it can detect mutations in gene.
• The technology holds promise through stem cell research and gene therapy and holds applications in forensic medicine.
• The technique may be helpful in developing useful and beneficial plants. It overcomes the limitations of traditional plant breeding. The techniques of plant tissue culture, transgenics, and marker-assisted selections are largely used for selecting better yielding varieties and imparting quality traits in plants.
• Food industries. Production of single-cell protein, spirulina, enzymes, and solid-state fermentations
• Increase and improvement of agricultural production
• Production of therapeutic pharmaceuticals
• Production of vaccines and monoclonal antibodies
• Cultivation of virus for vaccine production

Multiple Choice Questions

• All of the above
• Vitamin D and calcium
• Growth hormone
• Tissue plasminogen activator
• Factor VIII
• Genetically modifying organism
• Production of therapeutics
• Production of better diagnosis
• Increase in yield of crops
• Improved crop varieties
• Lesser fertilizers and agrochemicals
• All of these
• It is resistant to it.
• The toxin is enclosed in vesicle.
• The toxin is present in inactive form.
• None of these.
• Gene therapy
• Replacement protein therapy
• Stem cell therapy
• The productivity would improve.
• The usage of chemical agent would be reduced.
• The environment and crop would be insecticide free.
• All of the above.
• Detoxifying waste material
• Burying waste material
• Burning waste material
• None of these

(1) In all the cells of our body, all the genes are active.

(2) In different cells of our body, different genes are active.

(3) Gene expression is spatially and temporally regulated.

• All 1, 2, and 3 are correct.
• 1 and 2 are correct.
• 1 and 3 are correct.
• 2 and 3 are correct.
• Inoculation with monoclonal antibody was able to prevent small pox.
• Inoculation with pus from sores due to cowpox could prevent small pox.
• Attenuated vaccine was able to prevent small pox.
• None of the above.
• 1. (c); 2. (a); 3. (c); 4. (d); 5. (d); 6. (d); 7. (c); 8. (a); 9. (d); 10. (a); 11. (d); 12. (b)

Review Questions

• Q1. What are cry proteins? What is their importance?
• Q2. Give some applications of biotechnology in agriculture.
• Q3. What is your opinion about labeling of biotechnology-based food product as rDNA technology derived product?
• Q4. What are applications of biotechnology in maintaining environment?
• Q5. What is medical biotechnology?
• Q6. What are the challenges faced by biotechnology industry?
• Q7. What do you think about GM crops?

Some Related Resources

• http://ificinfo.health.org/backgrnd/BKGR14.htm
• http://www.bio.org/aboutbio/guide1.html
• http://www.bio.org/aboutbio/guide2000/guide00_toc.html
• http://www.bio.org/aboutbio/guide3.html
• http://www.bio.org/aboutbio/guide4.html
• http://www.dec.ny.gov/energy/44157.html
• http://www.ers.usda.gov/whatsnew/issues/biotech/define.htm
• http://www.nal.usda.gov/bic/bio21
• http://www.nature.com/nbt/press_release/nbt1199.html
• www.angelfire.com/scary/intern/links.html
• www.bio-link.org/library.htm
• www.biospace.com
• www.dnai.org
• www.fiercebiotech.com
• www.iastate.edu
• www.icgeb.trieste.it
• www.ncbi.nlm.nih.gov

• Search by keyword
• Search by citation

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• ISSN: 2090-5920 (electronic)

• Introduction
• Conclusions
• Article Information

A symptom was included if at least 5% of infected or uninfected participants reported experiencing that symptom. Adjusted odds ratios and risk differences were estimated from models that included infection status as the exposure and the presence of each prolonged symptom as the outcome, with adjustment for sex assigned at birth and race and ethnicity (see eMethods in Supplement 3 ).

A, Least absolute shrinkage and selection operator (LASSO) was used to fit a logistic regression model to identify which symptoms could be used to identify individuals likely to have PASC. Estimated log odds ratios were divided by 0.10 and rounded up to the nearest 0.5 to calculate symptom scores. An individual’s PASC research index is calculated by summing the scores for each prolonged symptom a participant reported (ie, the participant experienced the symptom for 4 weeks since the beginning of the pandemic and is currently experiencing it at the time of the survey). B, The optimal index threshold for PASC was selected using bootstrapping to estimate standard error bars. An approximation of the “elbow” method was used to identify the cutoff where the number of uninfected participants misclassified as PASC-probable stabilized (eMethods in Supplement 3 ). The threshold (index of at least 5.5) can be used to identify school-age children with PASC for research purposes. Using this threshold, the percentage of infected PASC-probable school-age children with each symptom was as follows: headache, 55%; trouble with memory or focusing, 45%; trouble sleeping, 44%; stomach pain, 43%; nausea or vomiting, 34%; back or neck pain, 30%; itchy skin or skin rash, 29%; fear about specific things, 26%; feeling lightheaded or dizzy, 26%; and refusing to go to school, 23%. C, Participant responses to 3 questions from the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 survey, stratified into 7 groups: participants with a zero PASC research index and no prolonged symptoms, zero PASC research index but at least 1 prolonged symptom, and participants with nonzero PASC index, divided into quintiles. The dark vertical line indicates the index threshold for PASC. Each cell is shaded according to the frequency of each response within each column, ranging from 0% to 100%.

A, Least absolute shrinkage and selection operator (LASSO) was used to fit a logistic regression model to identify which symptoms could be used to identify individuals likely to have PASC. Estimated log odds ratios were divided by 0.10 and rounded up to the nearest 0.5 to calculate symptom scores. An individual’s PASC research index is calculated by summing the scores for each prolonged symptom a participant reported (ie, the participant experienced the symptom for 4 weeks since the beginning of the pandemic and is currently experiencing it at the time of the survey). B, The optimal index threshold for PASC was selected using 95% CIs to estimate error bars. An approximation of the “elbow” method was used to identify the cutoff where the number of uninfected participants misclassified as PASC-probable stabilized (eMethods in Supplement 3 ). The threshold (index of at least 5) can be used to identify adolescents with PASC for research purposes. Using this threshold, the percentage of infected PASC-probable adolescents with each symptom was as follows: daytime tiredness/sleepiness or low energy, 80%; body, muscle, or joint pain, 61%; headache, 56%; trouble with memory or focusing, 47%; tired after walking, 42%; back or neck pain, 40%; feeling lightheaded or dizzy, 39%; and change or loss in smell or taste, 34%. C, Participant responses to 3 questions from the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 survey, stratified into 7 groups: participants with a zero PASC research index and no prolonged symptoms, zero PASC research index but at least 1 prolonged symptoms, and participants with nonzero PASC index, divided into quintiles. The dark vertical line indicates the index threshold for PASC (to the left is PASC-unspecified, to the right is PASC-probable). Each cell is shaded according to the frequency of each response within each column, ranging from 0% to 100%.

Symptoms, sorted from most to least common in the study population overall, are in the center column. Left columns correspond to school-age children in 3 groups: uninfected, infected and not meeting the PASC research index threshold (infected, PASC-unspecified), and infected and meeting the PASC research index threshold (infected, PASC-probable). The columns on the right correspond to adolescents with columns in the reverse order. Note that school-age children were not asked about panic attacks. Frequency of each prolonged symptom is indicated by shading, from 0% to 100%.

A and B, Subgroups formed using consensus clustering to group participants with similar symptom profiles (based on prolonged symptoms contributing to the PASC research index only). Four clusters were identified in PASC-probable school-age children and 3 clusters among adolescents. C and D, Frequencies of each prolonged symptom are shown for each cluster, where shading indicates frequency from 0%-100%. Symptoms that contribute to the PASC research index are above the dark horizontal line, and those below do not contribute to the PASC research index, sorted in decreasing frequency among all PASC-probable participants. Symptoms present in <5% of participants in every cluster were omitted. The full set of symptoms is in eFigure 6 in Supplement 3 .

Trial protocol

Statistical analysis plan

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Data sharing statement

• Uncovering Pediatric Long COVID JAMA Editorial August 21, 2024 Suchitra Rao, MBBS, MSCS

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Gross RS , Thaweethai T , Kleinman LC, et al. Characterizing Long COVID in Children and Adolescents. JAMA. Published online August 21, 2024. doi:10.1001/jama.2024.12747

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Characterizing Long COVID in Children and Adolescents

• 1 Division of General Pediatrics, Department of Pediatrics, NYU Grossman School of Medicine, New York
• 2 Department of Biostatistics, Massachusetts General Hospital, Boston
• 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts
• 4 Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
• 5 Bristol Myers Squibb Children’s Hospital, New Brunswick, New Jersey
• 6 Division of Infectious Diseases, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock
• 7 Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
• 8 Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
• 9 Division of Respiratory Medicine, Department of Pediatrics, UC San Diego School of Medicine, Rady Children’s Hospital, San Diego, California
• 10 Division of Child and Community Health, Department of Pediatrics, UC San Diego School of Medicine, Rady Children’s Hospital, San Diego, California
• 11 Departments of Cognitive Science, Psychiatry, and Radiology, UC San Diego School of Medicine, Rady Children’s Hospital, San Diego, California
• 12 School of Nursing, Virginia Commonwealth University, Richmond
• 13 Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles
• 14 Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles
• 15 Division of Cardiology, Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles
• 16 Department of Cardiology, Harvard Medical School, Boston, Massachusetts
• 17 Boston Children’s Hospital, Boston, Massachusetts
• 18 Division of Pediatric Cardiology, Department of Pediatrics, University of Utah, Primary Children’s Hospital, Salt Lake City
• 19 Division of General Pediatrics, Department of Pediatrics, University of California, San Francisco
• 20 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City
• 21 Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Massachusetts General Hospital, Boston
• 22 Brigham and Women’s Hospital, Boston, Massachusetts
• 23 Division of Neurology, Department of Neurology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
• 24 Massachusetts General Hospital, Boston
• 25 Division of Child Study Center, Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York
• 26 Department of Medicine, NYU Grossman School of Medicine, New York
• 27 Division of Pediatric Critical Care Medicine, Department of Pediatrics, NYU Grossman School of Medicine, New York
• 28 Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, New York
• 29 NYU Grossman School of Medicine, Bellevue Hospital Center, New York
• 30 Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, NYU Grossman School of Medicine, New York
• 31 RECOVER Patient, Caregiver, or Community Advocate Representative, New York, New York
• 32 Long Covid Families, Charlotte, North Carolina
• 33 Division of Long COVID, Department of Pandemic Equity, Vermont Center for Independent Living, Montpelier
• 34 Patient Led Research Collaborative, Washington, DC
• 35 CORe Community, Inc (COVID Recovery through Community, a 501c3), New York, New York
• 36 Division of Community Impact, Department of Health Strategies, American Heart Association, Atlanta, Georgia
• 37 Division of Biostatistics, Department of Medicine, Massachusetts General Hospital, Boston
• 38 Division of Child and Adolescent Health, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
• 39 Department of Population and Family Health, Mailman School of Public Health, New York-Presbyterian Hospital, New York
• Editorial Uncovering Pediatric Long COVID Suchitra Rao, MBBS, MSCS JAMA

Question   What prolonged symptoms experienced by youth are most associated with SARS-CoV-2 infection?

Findings   Among 5367 participants in the RECOVER-Pediatrics cohort study, 14 symptoms in both school-age children (6-11 years) and adolescents (12-17 years) were more common in those with vs without SARS-CoV-2 infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. Empirically derived indices for PASC research and associated clustering patterns were developed.

Meaning   This study developed research indices for characterizing pediatric PASC. Symptom patterns were similar but distinguishable between school-age children and adolescents, highlighting the importance of characterizing PASC separately in different age groups.

Importance   Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.

Objective   To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.

Design, Setting, and Participants   Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.

Exposure   SARS-CoV-2 infection.

Main Outcomes and Measures   PASC and 89 prolonged symptoms across 9 symptom domains.

Results   A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected ] and 147 without [referred to as uninfected ]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise–related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.

Conclusions and Relevance   This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Long COVID, or postacute sequelae of SARS-CoV-2 infection (PASC), has been broadly defined as symptoms, signs, and conditions that develop, persist, or relapse over time after SARS-CoV-2 infection. 1 , 2 These symptoms can last weeks, months, or years after the acute infection resolves and can have debilitating effects. Some experts believe that worldwide, an estimated 65 million people are living with PASC, 3 with impacts on population-level health anticipated to last for decades. Most research characterizing PASC has focused on adults, 4 leading to misperception that pediatric PASC is rare or presents similarly to PASC in adults. 5 , 6 This may lead clinicians to miss symptoms or misdiagnose children. Consistent with the life course framework in which developmental stage influences health outcomes, 7 PASC may present in both similar and different ways compared with adults.

Studies of pediatric PASC have documented a wide range of symptoms involving every organ system. 8 - 11 Most pediatric research has focused on individual symptoms and either pooled data from different ages or focused on adolescents. Little is known about differences in PASC symptoms between school-age children (6-11 years) and adolescents (12-17 years). 12 , 13 The absence of a consistent analytic approach to objectively identify children with PASC hinders the research needed to identify underlying mechanisms of disease and treatment targets. The National Institutes of Health–funded Researching COVID to Enhance Recovery ( RECOVER ) Initiative aims to fill these gaps by bringing together researchers, clinicians, communities, and families in a comprehensive study of PASC in children. 14 The aims of this analysis of the RECOVER-Pediatrics cohort were to identify (1) common prolonged symptoms experienced by children (6 to 17 years old) after SARS-CoV-2 infection, (2) how these symptoms differ by age (school-age vs adolescents), (3) how symptoms cluster into phenotypes, and (4) what symptoms in combination could be used as an empirically derived index to help researchers consistently assess the likely presence of PASC. These indices, like the one previously developed for the RECOVER-Adult cohort (18 years or older), 15 were intended to be used to identify factors that distinguish children who likely have developed PASC from those who may not have and to help evaluate risk factors for developing PASC, elucidate its pathophysiology, and enable follow-up to analyze recovery and relapse.

The RECOVER Pediatric Observational Cohort Study (RECOVER-Pediatrics) 14 is a combined retrospective and prospective longitudinal study including 4 cohorts. Data presented are from 2 cohorts: the de novo RECOVER cohort, including participants from birth through 25 years with and without SARS-CoV-2 infection history newly recruited from health care and community settings, and the extant National Institutes of Health–funded Adolescent Brain Cognitive Development cohort, 16 - 18 the largest long-term US study of brain development in adolescence. The protocol and statistical analysis plan for RECOVER-Pediatrics were previously described 19 (see Supplements 1 and 2 ). Data were obtained from more than 60 sites (eTable 1 in Supplement 3 ). The study received institutional review board approval from NYU Grossman School of Medicine (de novo cohort) or UC San Diego Human Research Protections Program (Adolescent Brain Cognitive Development cohort), with other institutions relying on these single institutional review boards. Caregiver-child pairs provided informed consent and age-appropriate assent. Strengthening and Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.

The analytic sample included individuals aged 6 to 17 years enrolled between March 16, 2022, and December 16, 2023, with and without known SARS-CoV-2 infection history ( infected and uninfected , respectively). Child age was recorded at symptom survey completion.

For these analyses, the infected group included participants who completed their survey about prolonged symptoms at least 90 days after their first infection, reported by their caregivers (eMethods in Supplement 3 ). SARS-CoV-2 antibodies were not required. The uninfected group was defined by caregiver report and required confirmation of negative nucleocapsid antibodies at enrollment. Those thought to be uninfected but found to be antibody-positive (Ab+) within 30 days of survey completion were analyzed separately to understand asymptomatic infection. 20 Throughout, uninfected refers strictly to uninfected participants who were confirmed to be nucleocapsid antibody–negative.

Infected participants with an unknown date for their first infection, participants with history of multisystem inflammatory syndrome in children (because this is a well-characterized entity), 21 - 25 uninfected participants without antibody testing, and participants with missing symptom surveys (defined as <50% of questions completed) were excluded.

Caregivers completed a comprehensive symptom survey remotely (interviewer-administered if needed) assessing 89 prolonged symptoms across 9 domains, using health literacy–informed principles and plain-language descriptions (eTable 2 in Supplement 3 ). 19 , 26 Some symptoms describing a similar phenotype were combined into composites, resulting in 75 symptoms (eMethods in Supplement 3 ): general (12 symptoms), eyes/ears/nose/throat (15 symptoms), heart/lungs (10 symptoms), gastrointestinal (6 symptoms), dermatologic (5 symptoms), musculoskeletal (3 symptoms), neurologic (6 symptoms), behavioral/psychological (14 symptoms), and menstrual (4 symptoms). The same symptoms were assessed in both age groups (except panic attacks, which were assessed in adolescents only). Menstrual symptoms were assessed in those assigned female or intersex at birth and who started menstruating (reported only among adolescents).

The primary outcome was a prolonged symptom lasting for more than 4 weeks that started or became worse since the beginning of the pandemic and was present at the time of survey completion (at least 90 days after infection). If a symptom lasted for more than 4 weeks but was absent at survey completion, it was not counted as a prolonged symptom.

Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Scales were assessed, measuring caregiver perception of the child’s overall health, physical health, and quality of life. 27

The main exposure variable was SARS-CoV-2 infection. Other variables included sex, race and ethnicity, geographic origin, time since SARS-CoV-2 infection, calendar time of enrollment, and SARS-CoV-2 vaccination status (eMethods in Supplement 3 ). Like other variables, race and ethnicity were collected via caregiver report based on prespecified categories and measured to enhance understanding of racial and ethnic differences in PASC. Caregiver variables included relationship to child and educational attainment.

Statistical analyses were modeled after those published for RECOVER-Adult and were age-stratified. 15 The analysis calculated the proportion of participants who reported each prolonged symptom and who reported experiencing at least 1 prolonged symptom among infected and uninfected participants separately (eTable 3 in Supplement 3 ). For symptoms present in at least 5% of infected participants (candidate symptoms), the risk difference, odds ratio, and relative risk for infected vs uninfected participants were estimated using linear, logistic, and Poisson regression, respectively, adjusting for sex and race and ethnicity (eMethods in Supplement 3 ). Second, to identify combinations of symptoms that could be used for research, a penalized logistic regression approach (least absolute shrinkage and selection operator [LASSO]) 28 was used to identify what candidate symptoms (predictors) were best at differentiating participants with or without an infection history (outcome). 15 Because all sexes were combined for this analysis, menstrual symptoms were excluded. Based on the model fit, each symptom was assigned a score corresponding to the estimated log odds ratio, where a higher symptom score indicated a stronger association with infection. A total index was calculated for each participant by summing the individual scores for each symptom reported. An optimal index threshold for identifying PASC was selected based on the proportion of uninfected participants who were likely misclassified as having PASC (eMethods in Supplement 3 ). Participants meeting the index threshold were categorized as PASC-probable and others were categorized as PASC-unspecified . PASC rates were reported among infected and uninfected participants separately. Among infected participants, these rates were also reported by whether they were infected by December 1, 2021 (when the Omicron variant became the dominant US strain).

Third, the analysis examined correlations between PASC indices and caregiver-reported overall child health, quality of life, and physical health and symptoms selected by LASSO. Further, the frequency of all symptoms was reported in infected PASC-probable, infected PASC-unspecified, and uninfected participants separately. Fourth, symptom patterns were investigated among infected participants categorized as PASC-probable. Correlations between symptoms contributing to the PASC index among infected PASC-probable participants were calculated. K-means consensus clustering was performed based on symptoms contributing to the PASC index to identify distinct PASC symptom profiles. 29 The number of different systems affected among infected PASC-probable participants was then summarized by counting the systems in which at least 1 prolonged symptom was reported. Fifth, we summarized the characteristics and symptomatology of uninfected participants found to be Ab+.

This study included 751 infected and 147 uninfected school-age children and 3109 infected and 1369 uninfected adolescents (see cohort identification details in eFigure 1 in Supplement 3 ). The Table and eTable 4 in Supplement 3 contain demographic and infection history characteristics, respectively. eTable 5 in Supplement 3 contains demographic characteristics for the adolescent cohort, stratified by recruiting cohort (Adolescent Brain Cognitive Development vs de novo).

Overall, 45% of infected (338/751) and 33% of uninfected (48/147) school-age children and 39% of infected (1219/3109) and 27% of uninfected (372/1369) adolescents reported having at least 1 prolonged symptom. Twenty-six symptoms in infected school-age children and 18 symptoms in infected adolescents were prolonged in at least 5% of participants ( Figure 1 ). The lower 95% confidence bound of the adjusted odds ratio exceeded 0 for 14 symptoms in both school-age children and adolescents, with 4 additional symptoms in school-age children only and 3 in adolescents only ( Figure 1 ). The frequency of each symptom among infected participants did not differ after stratification into quintiles based on time between first infection and symptom survey date (eFigure 2 in Supplement 3 ).

The LASSO analysis identified 10 symptoms in school-age children and 8 in adolescents that were most associated with infection history ( Figures 2 A and 3 A). Optimal index thresholds of 5.5 in school-age children and 5.0 in adolescents were identified ( Figures 2 B and 3 B). Overall, 152 infected (20%) and 6 uninfected (4%) school-age children and 445 infected (14%) and 44 uninfected (3%) adolescents met or exceeded this index threshold (eTable 6 in Supplement 3 ). This percentage was higher for participants infected before vs after the emergence of Omicron (21% vs 14% for school-age children; 17% vs 7% for adolescents). Correlations between symptoms that contributed to the index are shown in eFigure 3 in Supplement 3 . Correlations between these symptoms and those that did not contribute to the index are shown in eTable 7 in Supplement 3 . Some uninfected participants may have met the index threshold due to misclassification or due to having other symptoms.

In both age groups, higher PASC research indices were correlated with worse PROMIS scores ( Figures 2 C and 3 C). The number of systems affected among infected PASC-probable participants (eFigure 4 in Supplement 3 ) indicated substantial multisystem burden.

Figure 4 shows the percentage of participants in each age group experiencing each symptom after stratification into 3 subgroups: infected PASC-probable, infected PASC-unspecified, and uninfected. The most common prolonged symptom among PASC-probable school-age children that also contributed to the PASC research index ( Figures 2 B and 4 ) was headache (57%), followed by trouble with memory/focusing and trouble sleeping (44%) and stomach pain (43%). Among symptoms that did not contribute to the index, body/muscle/joint pain (51%), daytime tiredness/sleepiness or low energy (49%), and feeling anxious (47%) were the most common ( Figure 4 ). The distribution of symptoms was similar between PASC-unspecified and uninfected school-age children.

Among PASC-probable adolescents, the most common prolonged symptoms contributing to the index ( Figures 3 B and 4 ) were daytime tiredness/sleepiness or low energy (80%), body/muscle/joint pain (60%), headaches (55%), and trouble with memory/focusing (47%). Among symptoms that did not contribute to the index, trouble sleeping (47%), feeling anxious (47%), and feeling sad/depressed (38%) were the most common ( Figure 4 ). The distribution of symptoms was similar between PASC-unspecified and uninfected adolescent participants.

Among school-age children, 4 symptom clusters were identified ( Figure 5 ). Cluster 1 had high rates of many symptoms and the highest symptom burden. Cluster 2 was characterized by high rates of headache (95%), body/muscle/joint pain (60%), and daytime tiredness/sleepiness or low energy (52%). Cluster 3 was characterized by higher rates of trouble sleeping (64%) and trouble with memory/focusing (62%). Cluster 4 was characterized predominantly by stomach pain (100%) and nausea/vomiting (61%). Among adolescents, 3 clusters were identified ( Figure 5 ). Cluster 1 had high rates of many symptoms, similar to the first school-age cluster. Cluster 2 was characterized by high rates of daytime tiredness/sleepiness or low energy (89%) and body/muscle/joint pain (87%). Cluster 3 was characterized by having change/loss in smell or taste (100%), with relatively low rates of all other symptoms. The clusters with the most symptoms in both school-age children and adolescents (cluster 1) had the highest mean number of systems affected (eTable 8 in Supplement 3 ) and were correlated with poorer overall health and quality of life (eFigure 5 in Supplement 3 ).

Overall, 64 school-age children and 781 adolescents enrolled as uninfected but were Ab+ (ie, asymptomatically infected; eFigure 1 and eTable 9 in Supplement 3 ). Among school-age children, 6 (9%) met the index threshold whereas 18 (28%) reported experiencing at least 1 prolonged symptom. Among adolescents, 29 (4%) met the index threshold and 175 (22%) reported at least 1 prolonged symptom.

Symptom frequencies for all groups (infected, uninfected, and uninfected Ab+), including estimated risk ratios and odds ratios, are shown in eTable 10 in Supplement 3 .

In this large-scale study, children with probable PASC experienced prolonged symptoms in almost every organ system, with the majority having multisystem involvement. A clear pattern of symptom differences was identified between school-age children and adolescents, underscoring the importance of characterizing PASC separately in these 2 age groups.

This study developed an empirically derived index that can be used to help researchers identify children likely to have PASC, which was associated with overall health, physical health, and quality of life. This PASC research index, distinct for each age group, used combinations of 10 symptoms in school-age children and 8 symptoms in adolescents to indicate the likelihood of PASC. Although many other symptoms were more common in infected compared with uninfected participants, symptoms selected for the index were those that were most associated with infection history. Because these other symptoms were highly associated with the symptoms selected for the index (eTable 7 in Supplement 3 ), it was rare for participants not meeting the index threshold to have these other symptoms ( Figure 4 ). In this cohort, 20% of infected school-age children exceeded the PASC symptom threshold, while 14% of adolescents exceeded the threshold. PASC symptoms clustered into 4 distinct clusters in school-age children and 3 in adolescents.

The PASC research index presents a framework for future studies and can be used as a continuous or binary outcome variable (based on derived thresholds) to determine risk factors for developing PASC and the trajectory of PASC and its resolution (or relapse). Although this provisional index may be used for research, it is not intended for clinical practice, and 1 symptom may be sufficient to indicate PASC in any given child.

This study makes a substantial contribution to the understanding of pediatric PASC. Most research to understand PASC symptoms has focused on adults, potentially due to the misperception that children were not severely affected by COVID-19, leaving childhood symptoms less understood. Most prior pediatric studies have relied on electronic health records. 30 , 31 The current study had the advantage of comprehensively assessing caregiver-reported symptoms across every organ system, examining them in combination, and comparing them directly to an uninfected seronegative control group. The symptoms identified as being related to PASC were associated with infection, not only symptoms that became more common during the pandemic.

This study identified separate PASC research indices for school-age children and adolescents based on symptoms most likely to differentiate between those with and without an infection history. Higher indices were correlated with worse functional outcomes, and those with indices meeting the PASC threshold reported many prolonged symptoms, not just those selected by LASSO. 28 The strongest differentiators of infection history in adults (RECOVER-Adult study) 15 and adolescents overlapped considerably. There was less overlap between adults and school-age children. These findings underscore the need for separate assessments in different age groups. This may be one reason that younger children with PASC are being undercounted in studies and/or undiagnosed clinically, although undercounting may also be due to younger children being less able to recognize and report symptoms. The pathophysiology behind these age-related differences warrants future study, given substantial changes in growth, development, immunological factors, and pubertal hormones that occur across the life course. 11

Among infected participants, there was a wide range of time elapsed between infection and survey completion (median [IQR] time was 501 [297-801] days for school-age children and 518 [333-810] days for adolescents). However, symptom frequency did not change meaningfully when comparing different times between infection and survey completion, underscoring the usefulness of the PASC index for any child in the postacute phase of SARS-CoV-2 infection.

Four symptom clusters in school-age children and 3 in adolescents were identified. In both age groups, there was a single cluster with high symptom burden (as in adults) and a cluster predominated by fatigue and pain symptoms. Other clusters differed by age. School-age children had a cluster with neuropsychological and sleep impacts and another with gastrointestinal predominance. Adolescents had a cluster that was primarily loss of taste and smell, 32 similar to that found in adults, which was not noted in the school-age clusters. Clusters predominated by respiratory symptoms were not identified, possibly related to community recruitment or few participants with severe acute illness. Future research should evaluate whether these pediatric clusters are associated with different pathophysiology from adults, 33 - 35 which will be critical for identifying the treatment targets needed for clinical trials. 36 - 40

This study has limitations. First, the research index is not intended for use in clinical practice to diagnose PASC. Rather it must be considered with clinical judgement because children may have PASC without meeting the index threshold. There are many prolonged symptoms that differ between those previously infected and uninfected with SARS-CoV-2 that are not part of this index. It remains unknown how many children with other diagnoses would have similar prolonged symptoms. This index may evolve over time with changing variants and population immunity. Although children with higher PASC indices report worse quality of life, the cross-sectional analyses preclude causal inference. If a symptom lasted more than 4 weeks but was absent at survey completion, it was not included as a prolonged symptom because this index was not meant to describe incidence. However, it can be used for longitudinal follow-up of recovery and relapse, which would not be possible if resolved symptoms were used in the calculations.

Second, the population prevalence of pediatric PASC cannot be determined with the current design because participants with more prolonged symptoms may have been more inclined to enroll. To mitigate differences that may have resulted from having an extant adolescent cohort, community outreach within the school-age group was encouraged.

Third, some participants in the infected and uninfected groups could have been misclassified. Infected participants were not required to have evidence of SARS-CoV-2 infection; this study relied on caregiver-reported COVID-19 infection history, given variable access to testing. Uninfected children were confirmed to not have SARS-CoV-2 antibodies, but it is possible that some may have been unknowingly infected without developing antibodies or their immunity waned. 41 Uninfected participants may have another postviral syndrome or other conditions that may have symptoms and even pathophysiology that overlaps with PASC. 42 Despite this uncertainty, important differences between infected and uninfected groups were detected.

Fourth, given that symptoms were caregiver-reported, recall bias is possible. In addition, caregiver perceptions of their adolescents’ symptoms may differ from those of the adolescents themselves. However, to enable valid comparisons across age groups, data collection methods were standardized. Future analyses will combine caregiver-reported surveys with objective measures collected during the in-person longitudinal study phase. 19

Fifth, this empirically derived index is a framework that identified commonalities for research purposes. Iterative adaptation of how PASC is assessed may occur as more RECOVER data are collected and as children are followed up. Future analyses will examine PASC symptoms in early childhood (birth to 5 years) and the effects of SARS-CoV-2 on worsening underlying conditions and increasing new conditions, 43 - 45 such as diabetes, 46 autoimmune diseases, 47 neurocognitive disorders, and postinfectious syndromes. 11

In this large-scale study, symptoms that characterized pediatric PASC differed by age group, and several distinct phenotypic PASC presentations were described. The research indices developed here will help researchers identify children and adolescents with high likelihood of PASC. Although these indices will require further research and validation, this work provides an important step toward a clinically useful tool for diagnosis with the ultimate goal of supporting optimal care for youth with PASC.

Accepted for Publication: June 4, 2024.

Published Online: August 21, 2024. doi:10.1001/jama.2024.12747

Corresponding Author: Rachel S. Gross, MD, MS, NYU Grossman School of Medicine, 462 First Ave, New York, NY 10016 ( [email protected] ).

RECOVER-Pediatrics Group Authors: Venkataraman Balaraman, MD; Amanda Bogie, MD; Hulya Bukulmez, MD; Allen J. Dozor, MD; Daniel Eckrich, MS; Amy J. Elliott, PhD; Danielle N. Evans, DHSc, MHA; Jonathan S. Farkas, MD; E. Vincent S. Faustino, MD, MHS; Laura Fischer, MPH; Sunanda Gaur, MD; Ashraf S. Harahsheh, MD; Uzma N. Hasan, MD; Daniel S. Hsia, MD; Gredia Huerta-Montañez, MD; Kathy D. Hummel, MSN; Matt P. Kadish, MD; David C. Kaelber, MD, MPH; Sankaran Krishnan, MD, MPH; Jessica S. Kosut, MD; Jerry Larrabee, MD; Peter Paul C. Lim, MD; Ian C. Michelow, MD; Carlos R. Oliveira, MD, PhD; Hengameh Raissy, PharmD; Zaira Rosario-Pabon, MS; Judith L. Ross, MD; Alice I. Sato, MD, PhD; Michelle D. Stevenson, MD, MS; Maria M. Talavera-Barber, DO; Ronald J. Teufel, MD, MSCR; Kathryn E. Weakley, MD, MSc; Emily Zimmerman, PhD, CCC-SLP; Marie-Abele C. Bind, PhD; James Chan, MA; Zoe Guan, PhD; Richard E. Morse, BA; Harrison T. Reeder, PhD; Natascha Akshoomoff, PhD; Judy L. Aschner, MD; Rakesh Bhattacharjee, MD; Lesley A. Cottrell, PhD; Kelly Cowan, MD; Viren A. D'Sa, MD; Alexander G. Fiks, MD, MSCE; Maria L. Gennaro, MD; Katherine Irby, MD; Manaswitha Khare, MD; Jeremy Landeo Guttierrez, MD, MPH; Russell J. McCulloh, MD, MS; Shalu Narang, MD; Manette Ness-Cochinwala, MD; Sheila Nolan, MD; Paul Palumbo, MD; Julie Ryu, MD; Juan C. Salazar, MD, MPH; Rangaraj Selvarangan, PhD; Cheryl R. Stein, PhD; Alan Werzberger, MD; William T. Zempsky, MD, MPH; Robin Aupperle, PhD; Fiona C. Baker, PhD; Marie T. Banich, PhD; Deanna M. Barch, PhD; Arielle Baskin-Sommers, PhD; James M. Bjork, PhD; Susan Y. Bookheimer, PhD; Sandra A. Brown, PhD; BJ Casey, PhD; Linda Chang, MD; Duncan B. Clark, MD, PhD; Anders M. Dale, PhD; Mirella Dapretto, PhD; Thomas M. Ernst, PhD; Damien A. Fair, PA-C, PhD; Sarah W. Feldstein Ewing, PhD; John J. Foxe, PhD; Edward G. Freedman, PhD; Naomi P. Friedman, PhD; Hugh Garavan, PhD; Dylan G. Gee, PhD; Raul Gonzalez, PhD; Kevin M. Gray, MD; Mary M. Heitzeg, PhD; Megan M. Herting, PhD; Joanna Jacobus, PhD; Angela R. Laird, PhD; Christine L. Larson, PhD; Krista M. Lisdahl, PhD; Monica Luciana, PhD; Beatriz Luna, PhD; Pamela A.F. Madden, PhD; Erin C. McGlade, PhD; Eva M. Müller-Oehring, PhD; Bonnie J. Nagel, PhD; Michael C. Neale, PhD; Martin P. Paulus, PhD; Alexandra S. Potter, PhD; Perry F. Renshaw, MD, PhD; Elizabeth R. Sowell, PhD; Lindsay M. Squeglia, PhD; Susan Tapert, PhD; Lucina Q. Uddin, PhD; Sylia Wilson, PhD; Deborah A. Yurgelun-Todd, PhD.

Affiliations of RECOVER-Pediatrics Group Authors: Department of Biostatistics, Massachusetts General Hospital, Boston (Chan, Guan, Morse, Reeder); Division of Respiratory Medicine, Department of Pediatrics, UC San Diego School of Medicine, Rady Children’s Hospital, San Diego, California (Bhattacharjee, Guttierrez, Ryu); Division of Biostatistics, Department of Medicine, Massachusetts General Hospital, Boston (Bind); Department of Pediatrics, Kapi'olani Medical Center for Women and Children, University of Hawaii, John A. Burns School of Medicine, Honolulu, Hawaii (Balaraman, Kosut); Department of Pediatrics, Oklahoma University Health Science Center, Oklahoma City (Bogie); Division of Pediatric Rheumatology, Department of Pediatrics, MetroHealth System, Cleveland, Ohio (Bukulmez); Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Department of Pediatrics, Boston Children's Health Physicians, New York Medical College, Valhalla (Dozor, Krishnan); Department of Biomedical Research Informatics Center, Nemours Children's Hospital Delaware, Wilmington (Eckrich); Avera Research Institute, Sioux Falls, South Dakota (Elliott); Division of Research, Department of Research Administration, Arkansas Children's Hospital, Little Rock (Evans, Hummel); Department of Pediatrics, NYU Grossman School of Medicine, New York City Health and Hospitals Bellevue, New York (Farkas); Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut (Faustino); Pediatric Research Office, University of Nebraska Medical Center, Omaha (Fischer); Division of Allergy, Immunology, and Infectious Diseases, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey (Gaur); Division of Cardiology, Department of Pediatrics, Children's National Hospital, The George Washington University School of Medicine & Health Sciences, Washington, DC (Harahsheh); Division of Infectious Diseases, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey (Hasan); Department of Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, Louisiana (Hsia); Division of Puerto Rico Testsite for Exploring Contamination Threats, Northeastern University, Boston, Massachusetts (Huerta-Montañez); Division of General Pediatrics, Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque (Kadish, Larrabee); Departments of Pediatrics, Internal Medicine, and Population and Quantitative Health Sciences, MetroHealth System, Cleveland, Ohio (Kaelber); Division of Infectious Diseases, Department of Pediatrics, University of South Dakota Sanford School of Medicine, Avera Research Institute, Sioux Falls (Lim); Division of Infectious Diseases, Department of Pediatrics, Connecticut Children's Medical Center, University of Connecticut School of Medicine, Hartford (Michelow, Salazar); Division of Infectious Diseases, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut (Oliveira); Division of Pulmonary, Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque (Raissy); Division of Puerto Rico Testsite for Exploring Contamination Threats, Department of Civil and Environmental Engineering, Northeastern University, Boston, Massachusetts (Rosario-Pabon); Division of Pediatrics Administration, Department of Pediatrics, Thomas Jefferson University, Nemours Children's Hospital Delaware, Philadelphia, Pennsylvania (Ross); Division of Infectious Disease, Department of Pediatrics, University of Nebraska Medical Center, Omaha (Sato); Division of Norton Children's Emergency Medicine, Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky (Stevenson); Department of Pediatrics, University of South Dakota Sanford School of Medicine, Avera Research Institute, Sioux Falls (Talavera-Barber); Department of Pediatrics, Medical University of South Carolina, Charleston (Teufel); Division of Norton Children's Infectious Diseases, Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky (Weakley); Division of Puerto Rico Testsite for Exploring Contamination Threats, Department of Communication Sciences & Disorders, Northeastern University, Boston, Massachusetts (Zimmerman); Department of Psychiatry, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, California (Akshoomoff, Jacobus, Tapert); Center for Discovery and Innovation, Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, New Jersey (Aschner); Department of Pediatrics, West Virginia University, Morgantown (Cottrell); Division of Pediatric Pulmonology, Department of Pediatrics, University of Vermont, Burlington (Cowan); Department of Developmental Pediatrics, Rhode Island Hospital, Providence (D'Sa); Division of General Pediatrics, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (Fiks); Public Health Research Institute, Departments of Medicine, Rutgers Robert Wood Johnson Medical School, Newark, New Jersey (Gennaro); Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock (Irby); Division of Hospital Medicine, Department of Pediatrics, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, California (Khare); Division of Pediatric Hospital Medicine, Department of Pediatrics, University of Nebraska Medical Center, Omaha (McCulloh); Cooperman Barnabas Medical Center, Livingston, New Jersey (Narang); Nicklaus Children's Hospital, Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, Miami, Florida (Ness-Cochinwala); Division of Infectious Diseases, Department of Pediatrics, Boston Children's Health Physicians, New York Medical College, Valhalla (Nolan); Divisions of Infectious Disease and International Health, Departments of Pediatrics and Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (Palumbo); Department of Pediatrics, Children's Mercy Hospital and Clinics, Kansas City, Missouri (Selvarangan); Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York (Stein); Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, Best Healthcare Inc, Monroe, New York (Werzberger); Department of Pediatrics, Connecticut Children's Medical Center, University of Connecticut School of Medicine, Hartford (Zempsky); Laureate Institute for Brain Research, Tulsa, Oklahoma (Aupperle, Paulus); Center for Health Sciences, SRI International, Menlo Park, California (Baker, Müller-Oehring); Institute of Cognitive Science and Department of Psychology and Neuroscience, University of Colorado Boulder (Banich); Departments of Psychological & Brain Sciences, Psychiatry, and Radiology, Washington University in St Louis, St Louis, Missouri (Barch); Department of Psychology, Yale University, New Haven, Connecticut (Baskin-Sommers, Gee); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond (Bjork); Department of Psychiatry and Biobehavioral Sciences, University of Southern California, Children's Hospital Los Angeles (Bookheimer, Dapretto, Uddin); Department of Psychology and Psychiatry, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, California (Brown); Department of Psychology, Barnard College - Columbia University, New York, New York (Casey); Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland Baltimore (Chang, Ernst); Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania (Clark, Luna); Departments of Neurosciences, Radiology, and Psychiatry, UC San Diego School of Medicine, Rady Children's Hospital, San Diego, California (Dale); Institute of Child Development, Department of Pediatrics, Masonic Institute for the Developing Brain, University of Minnesota, Oregon Health & Science University, Minneapolis (Fair); Department of Psychology, University of Rhode Island, Kingston (Feldstein Ewing); Deptartment of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine, Rochester, New York (Foxe, Freedman); Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado Boulder (Friedman); Department of Psychiatry, University of Vermont, Burlington (Garavan); Department of Psychology, Florida International University, Miami (Gonzalez); Division of Addiction Sciences, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston (Gray, Squeglia); Department of Psychiatry, University of Michigan, Ann Arbor (Heitzeg); Department of Population and Public Health Sciences, University of Southern California, Children's Hospital Los Angeles (Herting); Department of Physics, Florida International University, Miami (Laird); Department of Psychology, University of Wisconsin-Milwaukee (Larson, Lisdahl); Department of Psychology, University of Minnesota, Minneapolis (Luciana); Department of Psychiatry, Washington University in St Louis, St Louis, Missouri (Madden); Departments of Psychiatry and Veteran Affairs, MIRECC, University of Utah School of Medicine, Salt Lake City (McGlade, Renshaw, Yurgelun-Todd); Department of Psychiatry, Oregon Health & Science University, Portland (Nagel); Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond (Neale); Division of Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont, Burlington (Potter); Department of Pediatrics, University of Southern California, Children's Hospital Los Angeles (Sowell); Institute of Child Development, University of Minnesota, Minneapolis (Wilson).

Author Contributions: Drs Thaweethai and Foulkes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gross and Thaweethai contributed equally as co–first authors and Drs Foulkes and Stockwell contributed equally as co–senior authors.

Concept and design: Gross, Thaweethai, Kleinman, Snowden, Milner, Tantisira, Rhee, Jernigan, Kinser, Salisbury, Warburton, Mohandas, Flaherman, Metz, Karlson, Chibnik, Pant, Gallagher, Gennaro, Lamendola-Essel, Katz, Yin, Dreyer, Carmilani, Coombs, Fitzgerald, Taylor, Evans, Huerta-Montanez, Kaelber, Oliveira, Raissy, Reeder, Baker, Brown, Dale, D'Sa, Fair, Lisdahl, Luna, McGlade, Renshaw, Foulkes, Selvarangan, Stockwell, Yurgelun-Todd.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gross, Thaweethai, Snowden, Kinser, Warburton, Mohandas, Krishnamoorthy, Gallagher, Katz, Carmilani, Coombs, Fitzgerald, Taylor, Eckrich, Raissy, Ross, Sato, Feldstein Ewing, Paulus, Stockwell, Squeglia.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Fischer, Thaweethai, Chibnik, Pant, Krishnamoorthy, Letts, Sato, Reeder, Teufel, Neale, Bind, Chan, Foulkes.

Obtained funding: Gross, Thaweethai, Kleinman, Rosenzweig, Tantisira, Rhee, Jernigan, Kinser, Salisbury, Warburton, Katz, Elliott, Raissy, Aschner, Baker, Barch, Baskin-Sommers, Bjork, Bookheimer, Casey, Chang, Clark, Dale, Dapretto, Ernst, Fair, Feldstein Ewing, Foxe, Friedman, Gee, Gonzalez, Gray, Herting, Jacobus, Laird, Lisdahl, Luciana, Muller-Oehring, Nagel, Neale, Paulus, Renshaw, Salazar, Selvarangan, Stockwell, Tapert, Wilson.

Administrative, technical, or material support: Fischer, Gross, Hasan, Hsia, Kadish, Kleinman, Kosut, Snowden, Milner, Rhee, Jernigan, Warburton, Wood, Truong, Flaherman, Karlson, Gallagher, Lamendola-Essel, Hasson, Katz, Taylor, Teufel, Eckrich, Evans, Farkas, Faustino, Huerta-Montanez, Jacobus, Kaelber, Krishnan, Raissy, Morse, Cottrell, Fiks, Landeo Guttierrez, Ness-Cochinwala, Ryu, Stein, Baskin-Sommers, Aupperle, Brown, Bukulmez, Chan, Chang, Clark, Dale, Dozor, Ernst, Foxe, Freedman, Garavan, Gee, Laird, Lisdahl, McGlade, Paulus, Renshaw, Salazar, Stevenson, Squeglia, Uddin, Werzberger.

Supervision: Gross, Hsia, Thaweethai, Kleinman, Snowden, Rhee, Jernigan, Kinser, Warburton, Mohandas, Wood, Chibnik, Lamendola-Essel, Katz, Kaelber, Krishnan, Oliveira, Cottrell, Ness-Cochinwala, Akshoomoff, Aschner, Banich, Baskin-Sommers, Brown, Bukulmez, Chan, Chang, Clark, Dozor, Gee, Heitzeg, Herting, Hummel, Larrabee, Lisdahl, McGlade, Nolan, Renshaw, Fiks, Foulkes, Jacobus, Larson, Luciana, Salazar, Sowell, Stockwell, Teufel, Werzberger, Yurgelun-Todd.

Other - discussions of findings: Gallagher.

Other - communication of scientific findings: Fitzgerald.

Other - Contributed experience and knowledge from the patient/caregiver, and Infection Associated Chronic Condition community, perspective: Letts.

Conflict of Interest Disclosures: Dr Kleinman reported receiving grants from New York University via subcontract of NIH during the conduct of the study; owning shares in Amgen, Regeneron, Sanofi, and GLAXF; and being a member of the board of Dartnet Institute and member of the board of health of Borough of Metuchen, Quality Matters, Inc . Dr Snowden reported serving on a Pfizer COVID-19 advisory board, which ended in November 2023. Dr Milner reported serving on a scientific advisory board for Blueprint Medicine and receiving grants from Pharming. Dr Jernigan reported receiving grants from University of California San Diego OTA during the conduct of the study. Dr Salisbury reported receiving grants from NIH and HRSA and donated funds from Anthem outside the submitted work. Dr Newburger reported receiving grants from Pfizer for an observational study on COVID-19 associated myocarditis, serving on a data and safety monitoring committee for BMS, and serving on an independent events adjudication committee for pediatric apixiban study outside the submitted work. Dr Truong reported being co–principal investigator on a Pfizer-funded study to assess long-term sequalae of vaccine-associated myocarditis. Dr Metz reported being a site principal investigator for Pfizer studies of SARS-CoV-2 vaccination in pregnancy, RSV vaccination in pregnancy, and Paxlovid in pregnancy. Dr Dreyer reported receiving grants from NYU Grossman School of Medicine during the conduct of the study. Dr Aschner reported being a stockholder in Gilead Sciences. Dr Bhattacharjee reported serving on an advisory board for Jazz Pharmaceuticals. Dr Werzberger reported receiving funding from Merck for a hepatitis A vaccine immunology study. Dr Zempsky reported affiliations with OmmioHealth, Lundbeck Pharmacueticals, and Editas. Dr Banich reported receiving grants from University of Colorado Boulder during the conduct of the study. Dr Barch reported receiving grants from NIMH and NIDA during the conduct of the study. Dr Bhattacharjee reported consulting for Jazz Pharmaceuticals and Avadel Pharmaceuticals outside the submitted work. Dr Dale reported being a founder of and holding equity in CorTechs Labs, Inc; serving on a scientific advisory board for CorTechs Labs, Inc, Human Longevity, Inc, and the Mohn Medical Imaging and Visualization Centre; and receiving funding through a research agreement with General Electric Healthcare (GEHC). Dr Fair reported being a patent holder for the Framewise Integrated Real-Time Motion Monitoring (FIRMM) software and a cofounder of Turing Medical, Inc. Dr Fiks reported receiving personal fees from Rutgers and salary support from AAP during the conduct of the study; receiving support from American Medical Association for travel and honorarium from Atlantic Health Systems and Boston Medical Center, PCORI, and Emory University; and having a patent for decision support software known as Care Assistant pending. Dr Foulkes reported receiving grants from NIH/NHLBI during the conduct of the study. Dr Gray reported receiving grants from Aelis Farma and personal fees from Indivior and Jazz Pharmaceuticals outside the submitted work. Dr McCulloh reported receiving grants from University of Arkansas for Medical Sciences sub-awardee for the NIH RECOVER grant during the conduct of the study and grants from Merck Foundation for vaccine communication research through the Merck Investigator Studies Program outside the submitted work. Dr McGlade reported receiving salary support from Department of Veteran Affairs outside the submitted work. Dr Neale reported receiving grants from NIH/NIDA during the conduct of the study. Dr Palumbo reported being a member of a data and safety monitoring committee for Gilead and Janssen outside the submitted work. Dr Paulus reported receiving grants from National Institute on Drug Abuse during the conduct of the study, receiving royalties from an article on methamphetamine in UpToDate, and having compensated consulting agreement with Boehringer Ingelheim International GmbH. Dr Ross reported receiving grants from Nemours Children’s Health-DE NIH RECOVER STUDY during the conduct of the study. Dr Stockwell reported receiving grants from CDC to Trustees of Columbia related to SARS-CoV-2 infection and vaccination research and service agreement paid to trustees of Columbia for being associate director of pediatric research in office settings from American Academy of Pediatrics outside the submitted work. Dr Teufel reported receiving grants from HRSA and Duke outside the submitted work. No other disclosures were reported.

Funding/Support: This research was funded by NIH agreements OT2HL161841, OT2HL161847, and OT2HL156812, with additional support from grant R01 HL162373.

Role of the Funder/Sponsor: The NIH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The RECOVER-Pediatrics Consortium appear listed in Supplement 4 .

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the RECOVER Program or the NIH.

Data Sharing Statement: See Supplement 5 .

Additional Contributions: We would like to thank the National Community Engagement Group, all patient, caregiver, and community representatives, and all the participants enrolled in the RECOVER Initiative.

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Lykos' woes mount as FDA expands probe into its MDMA-based research: WSJ

For Lykos Therapeutics and the company’s would-be MDMA-assisted therapy for post-traumatic stress disorder (PTSD), the hits just keep coming. 

Earlier this month, Lykos was struck by an FDA rejection, research paper retractions and layoffs. Now, the FDA is looking into certain studies sponsored by the company, The Wall Street Journal reports .

The FDA is widening its scrutiny of the clinical trials testing Lykos’ recently rejected drug and last week interviewed at least four people about the Lykos-sponsored studies, according to WSJ, which cited individuals close to the matter. 

FDA investigators specifically asked about whether side effects went unreported in the studies, the newspaper explained. 

“Lykos is committed to engaging with the FDA and addressing any questions it raises,” a company spokesperson told WSJ. She added that the biotech looks forward to meeting with the FDA about issues raised as part of its recent PTSD rejection.

Lykos has been on a roller coaster ride ever since the FDA snubbed its midomafetamine (MDMA) therapy in patients with PTSD earlier this month. The company was seeking approval of its MDMA capsule along with psychological intervention, also known as MDMA-assisted therapy. 

At the time, the regulator requested that Lykos run another phase 3 study to garner more data on the safety and efficacy of MDMA-assisted therapy for PTSD. Lykos, for its part, said it planned to meet with the FDA to ask the agency to reconsider its decision. 

Shortly thereafter, the journal Psychopharmacology yanked three articles about midstage clinical trial data weighing Lykos’ investigational MDMA therapy, citing protocol violations and “unethical conduct” at one of the biotech’s study sites.   

According to retraction notices issued around the middle of August, the authors whose names were attached to the papers confirmed they were aware of the protocol violations when the articles were submitted for publication but never mentioned them to the journal or excluded the data sourced from the site in question. 

Psychopharmacology’s retraction decision also raised issues around a previously known case of “unethical therapist conduct” tied to a phase 2 study in 2015, Lykos told Fierce Biotech earlier this month. 

The company said it disagreed with the retraction decision and believed the issue would have been better solved through corrections. 

“Lykos has filed an official complaint with the Committee on Publication Ethics (COPE) to review the process through which the journal came to this decision,” a company spokesperson said at the time. 

Meanwhile, capping off Lykos’ turbulent month, the company recently said it would lay off about 75% of its staff in the aftermath of the FDA snub. 

Rick Doblin, Ph.D., the founder and president of Lykos’ parent MAPS, also decided to exit his position on the Lykos board. 

Lykos’ argued that the job cuts, which will affect about 75 people, would help the company focus on its goal of getting its MDMA-assisted therapy across the regulatory finish line.

The employees who will retain their jobs will prioritize ongoing clinical development, medical affairs and engagement with the FDA, according to a Lykos release.  

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Computer Science > Artificial Intelligence

Title: automated design of agentic systems.

Abstract: Researchers are investing substantial effort in developing powerful general-purpose agents, wherein Foundation Models are used as modules within agentic systems (e.g. Chain-of-Thought, Self-Reflection, Toolformer). However, the history of machine learning teaches us that hand-designed solutions are eventually replaced by learned solutions. We formulate a new research area, Automated Design of Agentic Systems (ADAS), which aims to automatically create powerful agentic system designs, including inventing novel building blocks and/or combining them in new ways. We further demonstrate that there is an unexplored yet promising approach within ADAS where agents can be defined in code and new agents can be automatically discovered by a meta agent programming ever better ones in code. Given that programming languages are Turing Complete, this approach theoretically enables the learning of any possible agentic system: including novel prompts, tool use, control flows, and combinations thereof. We present a simple yet effective algorithm named Meta Agent Search to demonstrate this idea, where a meta agent iteratively programs interesting new agents based on an ever-growing archive of previous discoveries. Through extensive experiments across multiple domains including coding, science, and math, we show that our algorithm can progressively invent agents with novel designs that greatly outperform state-of-the-art hand-designed agents. Importantly, we consistently observe the surprising result that agents invented by Meta Agent Search maintain superior performance even when transferred across domains and models, demonstrating their robustness and generality. Provided we develop it safely, our work illustrates the potential of an exciting new research direction toward automatically designing ever-more powerful agentic systems to benefit humanity.

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