Translational Research - an overview (2023)

Outcomes Translational Research

The practice of surgery has changed greatly since its early beginnings. Issues of anatomy, physiology, and anesthesia gave way to improving technology and the refinement of surgical technique. As surgeons gained technical skill and collective expertise, clinical outcomes and evidence-based medicine began to take on increasing importance. The proliferation of surgical care (and medicine as a whole) does come with a cost, however. In the United States, healthcare expenditures for the year 2014 reached $3 trillion, or approximately $9523 per person or 17.5% of the gross national product. Other developed countries spend less, but their expenditures are increasing.

Although the actual care of patients will continue to challenge us, the way we conduct and finance healthcare will also have a profound impact. Healthcare is a continuum from advancements in basic sciences, patient applications, clinical outcomes, efficacy analysis, and policy. The ultimate goal of the many tools described here is to improve patient care. Wheretranslational research captures the connection between the basic sciences and patient care,outcomes translational research can be thought of as the connection between clinical outcomes and healthcare policy. Policy decisions based on expenditure caps can control healthcare costs. However, if these decisions are made arbitrarily, the resulting distribution of resources may be inefficient. Ideally, healthcare policy should be based on clinical evidence and efficacy should maximize limited resources.

Outcomes translational research begins with a careful analysis of clinical results. Such an analysis should ideally incorporate carefully designed studies to elucidate the natural history of a disease and compare treatment options. Even the outcome measure itself needs thoughtful selection. For example, in the surgical treatment of claudication, the classic measure of outcome was bypass graft patency. With the greater adoption of percutaneous treatment methods, vessel patency has been adopted. However, vessel patency does not accurately reflect all outcomes. From the patient's perspective, symptom relief and improvement in QoL is the benchmark. Although vessel patency clearly influences walking function, a patent vessel does not confer improved walking if other comorbid conditions, such as severe arthritis or neuropathy, are limiting. Conversely, assessment of functional and QoL endpoints alone does not allow analysis of the components leading to patient-perceived improvements. Greater understanding of technical success, vessel patency, and treatment durability will allow further improvements in the treatments themselves. Therefore measurement of clinical outcomes is a multimodal technique involving the use of integrated components that measure several aspects of success and failure.

Although there is no doubt that the results of clinical trials have had an impact on the care of surgical patients, these trials are costly and may not have comprehensive generalizability. The majority of vascular surgery occurs outside of clinical trials, in institutions of varying size, and by practitioners of varying expertise. The outcomes of these “real world” efforts are not well studied and may not mirror the experience of large academic institutions. To begin to address healthcare at a population level, many have used large national or statewide administrative databases in an attempt to analyze care broadly. Although such efforts can be informative when they are used appropriately, it is often difficult to draw clinical recommendations from these databases, which are primarily based on billing rather than clinical information. Often limiting in vascular surgery, most administrative databases do not distinguish the left from the right extremity. Thus, two vascular procedures performed on an extremity within 1 year can represent a revision of the first procedure, or they can signify sequential bilateral procedures. Comprehensive registries that allow broader inclusion of patients who receive care within specific diagnostic groups have begun to address these issues. Although countries with single-payer healthcare are more easily able to establish national registries, databases comprising regional vascular surgery patients exist and have helped to inform vascular care. The cost of such endeavors is certainly a factor in achieving a nationwide database, although arguably the cost of not knowing the outcomes and efficacy of healthcare may be greater.

14 Translational research

Translational research is the “buzz word” for research today but it is a relatively new area of investigation. There was little thoughtful discussion of the ethics of translational research until well into the new century (Mandal et al., 2017; Rubio et al., 2010). Translational research moves from the laboratory bench, into the clinical research setting, into clinical care at the patient’s bedside, and back into the research setting. Translational research is designed to move basic research findings into therapeutics and to accelerate the flow of insights from clinicians that are shaped into questions answered at the bench and within the clinical research environment. Investigators can expect to see funding for translational research growing at a dizzying pace over the next several decades. One of the primary ethical concerns about this research relates to the types of contractual agreements that are attached to many of the studies and the concerns the agreements raise for continued free exchange of scientific information. That is, translational research is characterized by the kinds of public/private collaborations that can produce serious conflicts of interest for investigators and institutions. Another ethical concern raised by the push for translational research is that there will be a reduction in funding for undirected basic research. Because so much of medical and scientific progress results from serendipitous findings, directing scientific inquiry towards therapeutics may have an effect opposite to that which the proponents of translational research seek. By attempting to move basic research too quickly into areas that have a specific therapeutic focus, the natural meandering of scientific interest may be constrained, and the possibility that scientific surprises can emerge will ultimately be reduced. A final and related concern mentioned is that the push of translational research will result in moving science so quickly from the bench to the bedside and in so doing participants may be harmed in ways that might have been avoided had the process been slower. A glaring example of how this problem might evolve is discussed in the presentation of the research focused on brain tissue transplants in Parkinson’s Disease in Chapter 15. Moreover, there are other concerns to contend with as the push for translational research grips the research community. These include developing ethical processes for partnering with sick patients (Mamzer et al., 2017), minority communities (Estape-Garrastazu et al., 2014), establishing frameworks for mentorship in translational research (Abedin et al., 2012), and developing ways in which to evaluate how well a translational study performed (Trochim et al., 2011). These ethical issues, and the many others embedded into the performance of translational research may require a complete rethinking of the ethics of clinical research in the age of translational science (Hostiuc et al., 2016; Bærøe, 2014).

Conclusion

Translational research in aging has the potential to influence lifespan and healthspan beyond the boundaries of traditional disease-based research. There are many animal models and human cohorts that are useful in studying aging, but important limitations include marked differences among them that make translating animal findings to humans difficult, a number of key limitations that affect longitudinal studies in both humans and animals, and the need to study multimorbidity and complexity for translational research to be generalizable to most older adults. Focusing on healthspan rather than lifespan by including functional outcomes as endpoints is critical and requires experimental design and analysis plans unique to aging research. A number of resources are available from the NIA, the Centers for Disease Control and Prevention, and other agencies to assist translational research in this area.

16.2.1 Core facilities of prime significance in translational research

Translational research can especially benefit from various technological advances working in a coordinated and collaborative way. The cancer research community often comes across the challenge of translating laboratory findings and clinical research data into actual clinical outcomes to benefit the diagnosis, treatment, and prevention of cancer (McCabe, 1997). The McGill Centre Translational Research in Cancer (MCTRC) offers expertise covering a large spectrum, from biochemistry and drug design to immunotherapies and translational proteomics and artificial intelligence, and computer science applied to diagnostic methods (https://www.mcgill.ca/translational-research-cancer/core-facilities). This collaborative and open-access research environment makes MCTRC uniquely positioned to rapidly translate scientific discoveries to patients by leveraging expertise and creating new partnerships with critical stakeholders in the government, biotech, and pharma sector.

The Human Genome Project is considered one of the landmark discoveries initiating a whole new era of genomics, giving the world a wealth of detailed information about the structure, organization, and function of the complete set of human genes (Watson & Cook-Deegan, 1991). This led to further understanding of human biology and the advancement of various molecular techniques like proteomics, metabolomics, and microbiomics to understand and synthesize knowledge holistically. This multipronged approach leads to the development of potential novel diagnostic or drug discovery targets.

While research in proteomics defines the structure and function of proteins encoded by the genome of an organism, metabolomics uses the systematic analysis of the chemical fingerprints left behind by cellular processes (Daviss, 2005; Oliver, Winson, Kell, & Baganz, 1998; Wilkins, Williams, Appel, & Hochstrasser, 1997). Microbiomics, on the other hand, is the characterization of the human microbiota to learn its impacts on human health and disease (Rajendhran & Gunasekaran, 2010). Further, metagenomics, a relatively newer field in this realm, involves the characterization of the microbiome’s genomes, as well as their corresponding mRNA, protein, and metabolites [Gill et al., 2006; National Research Council (US) Committee on Metagenomics, 2007]. Together, these “omics” comprise an extensive toolkit in systems biology at the forefront of translational research.

These highly advanced technological platforms that can bring a significant impact in propelling translational research are the result of highly specialized interdisciplinary fields and require highly complex, advanced, and unique infrastructure. The accessibility and affordability of these technologies within a research lab serving the interest of an individual researcher would be a huge waste of investment. The post–genomic era saw rapid adoption of core facilities by many academic institutions primarily because of the huge cost associated with these technologies. In addition, it also needed a trained individual to run samples, and to continue to be updated on new sequencing technologies (Meder et al., 2016). These core facilities are open access to internal and external users and operate on a fee-for-service basis and essentially make research more affordable. The creation of these technology hubs that are shared across an institute/university, region, or even nation-wide removes the roadblocks in a translational research outcome by reducing the overall cost of establishing these infrastructures and increased accessibility. With a shared facility/core facility model, the research propels faster, leading to the final goal of providing better health solutions or discoveries.

In an extensive scan of technologies and resources catalyzing translational and clinical research, 52 generic areas were identified (Rosenblum, 2012). This comprised various traditionally relevant biomedical research cores like microscopy, flow cytometry, histopathology, high throughput screening, vaccine core, synthetic chemistry, biobank repositories, etc., while nanotechnology, in vitro fertilization, next-generation sequencing, single-cell sequencing, gene therapy, etc. are rapidly evolving platforms gaining significance in translational research (Rosenblum, 2012). A strategic and collaborative plan to connect the resources and expertise would bring immense returns to translational research advances and faster delivery of the desired outcome to public health.

The Role of Patient-Oriented Research in Translational Research

Translational research has traditionally referred to the translation of basic research findings to the clinical level, commonly termed ‘bench to bedside’. Patient-oriented research plays a central role in this translation in demonstrating whether basic findings in cells or in animals apply to humans. For example, human epidermal growth factor receptor (HER2) was shown to be overexpressed in tumors of ≈20% of women with breast cancer. Women with tumors overexpressing this receptor had poorer prognoses, with greater tumor invasion and metastases. A human monoclonal antibody to HER2 (trastuzumab) was developed in the laboratory and then, after clinical trials demonstrated trastuzumab added onto traditional chemotherapy led to improved survival in women with HER2-positive metastatic breast cancer, the US Food and Drug Administration approved this therapy (Sledge, 2004). Translational research is not unidirectional. Clinical observations from patients may inform both patient-oriented and basic investigation. Furthermore, a second translational step is receiving increasing attention: the translation of research findings from patient-oriented research such as clinical trials into daily clinical practice. The failure for translation into community care has been referred to as the second translational block (Sung et al., 2003). The recent development of the Clinical and Translational Science Awards (CTSAs) (see Chapter 11 for more details) reflect the importance that the NIH is placing on translational research. Thus, patient-oriented research plays a central role in the translation of basic research findings to eventual improvements in clinical practice and patient care.

B Translational Research

Translational research is generally viewed (Adams, 2008; Duyk, 2003; FitzGerald, 2005, 2007; LoRusso, 2009; Maienschein, Sunderland, Ankeny, & Robert, 2008; Wehling, 2008, 2009; Woolf, 2008b) as a “bench to bedside” discipline designed to direct the findings of basic research to the production of new medications (Woolf, 2008b). Translational research may also be viewed as important in fulfilling the desire of basic scientists to have their work used for the benefit of mankind (Wehling, 2008) and to ultimately reverse the decline in drug discovery productivity. Translational research has been further envisaged (i) a process for ensuring the bidirectional flow of information from the research laboratory to the clinic and vice versa (Sung et al., 2003) and (ii) as encompassing all elements of the drug development process from the initial screening for chemical leads to target identification to clinical proof of concept (FitzGerald, 2005). Many fear, however, that like the concept of target validation (Kopec et al., 2005), in its current form, the promise of translational medicine approach far exceeds the practicalities of what it can deliver in terms of facilitating the drug discovery process (Maienschein et al., 2008; Wehling, 2008). In FitzGerald’s view, the centerpieces of the translational effort are the academic medical centers (AMCs) responsible for conducting clinical trials. To this end, the NIH has sponsored Clinical and Translation Science Awards (CTSAs) as part of the Roadmap initiative with some $500 million being earmarked through 2012 to fund 60 AMCs across the United States (FitzGerald, 2009; Woolf, 2008b). Similar efforts are underway in the United Kingdom under the auspices of the National Institute for Health Research (Adams, 2008) and in Europe as the European Advanced Translational Research Infrastructure in Medicine Network (EATRIS) (Wehling, 2009; Woolf, 2008b). All these programs focus on improving the outcomes from drug discovery R&D to enhance medical care. However, it has been noted (FitzGerald, 2009) that the existing AMCs are much less efficient than traditional contract research organizations (Moos & Mirsalis, 2009) that conduct the majority of clinical trials for the pharmaceutical industry. This has been ascribed to a perceived lack of necessary career incentives that may be viewed as conflicting with the ethos of biomedical research (Harris, 2005).

A major contributor to the confusion around translational research involves the definitions of “translational blocks.” Termed T1 and T2 by the Institute of Medicine’s Clinical Research Roundtable (Sung et al., 2003; Woolf, 2008b), T1 is generically considered as representing the translational component and is defined as “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.” T2 involves translation in the context of the community and ambulatory care setting and is described as “the translation of results from clinical studies into everyday clinical practice and health decision making”. Support of T2, which has been argued as being in need of a new name and emphasis (Woolf, 2008b), is essential for T1 to be successful and also for patients to derive maximal benefit from delivered health care. T2 involves studies in the community and ambulatory care setting.

Definitional Issues

Translational Significance

Translational research pertains to the process of translating scientific discoveries into practical (clinical) applications. Next generation sequencing is playing a transformational role in cancer discovery and genetic disorder research. Providing new insights into disease mechanisms and metabolic and signaling pathways are examples of progress made through NGS that was not previously unfeasible. Related information is being used to improve diagnostics, and to develop more effective and more personalized treatments for disease and patient care.

Furthermore, targeted next generation sequencing holds great potential for speedy, wide-ranging mutational analysis to unravel complex tumor signature variations and improve the cost-effectiveness of sequencing by focusing on the portions of the genome that are relevant for the question of study. With decreasing costs and improving technology, NGS has the potential to translate enormous amounts of raw data into useful information in almost all aspects of research into health, development, and disease.

Translation and Qualification of Safety Biomarkers

Conclusion

Translational research has made many contributions to knowledge about the hepatotropic viruses, but knowledge gaps remain. The incidence and health care costs related to HAV should decrease dramatically with the use of the highly effective hepatitis A vaccine for all subjects 1 to 18 years old; universal vaccination for all adults as well may be a more practical strategy, rather than targeted immunization in high-risk groups. More effective strategies are needed to prevent maternal-to-fetal transmission of HBV because vaccine failures still occur in at least 10% of mother-infant pairs. New data have emerged in recent years on the natural history and treatment of chronic HBV infection in children, but antiviral resistance remains a main concern during long-term treatment of chronic HBV. Advances have been made in treatment of HCV in children, and promising results are seen with specifically targeted antiviral therapies. A novel hepatitis E vaccine was shown to be efficacious; however, more investigations to improve immunogenicity and safety are needed, especially for pregnant women, in whom morbidity and mortality are high. Close observations of HGV and TTV are needed to see if these viruses are truly of clinical significance.