Collateral Therapeutics Research Articles

The impact of collateral therapeutics on stroke hemodynamics in normotensive and hypertensive rats: a step toward translation.

Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy. We compared the efficacy of two different collateral therapeutics during transient middle cerebral artery occlusion (tMCAO) in normotensive and hypertensive rats. The change in collateral and core perfusion was measured using dual laser Doppler in response to either a pressor agent (phenylephrine, 10 mg/kg iv or vehicle) or a collateral vasodilator (TM5441, 5 mg/kg iv or vehicle) given 30 min into tMCAO in male Wistar and spontaneously hypertensive rats (SHRs). Pressor therapy increased collateral flow in the Wistar rats but was ineffective in the SHRs. The increase in collateral flow in the Wistar rats was associated with impaired cerebral blood flow autoregulation (CBFAR) that was intact in the SHRs. TM5441 caused a decrease in collateral perfusion in the Wistar rats and a modest increase in the SHRs. The pressor therapy reduced early infarction in both groups but increased edema in the SHRs, whereas TM5441 did not have any beneficial effects in either group. Thus, the pressor therapy was superior to a collateral vasodilator in increasing collateral flow and improving outcomes in the Wistar rats, likely due to pial collaterals that were pressure passive; the lack of CBF response in the SHRs to pressor therapy was likely due to intact CBFAR that limited perfusion. While TM5441 modestly increased CBF in the SHRs but not in the Wistar rats, it did not have a beneficial effect on stroke outcomes. These results suggest that collateral therapies may need to be selected for certain comorbidities.

The effect of head-down tilt in experimental acute ischemic stroke.

Collateral therapeutics exert a promising protective effect on the outcome of acute ischemic stroke. Cerebral blood flow (CBF) may be modulated by different head positioning. The current study aimed to determine the effect of head-down tilt (HDT) on stroke in a rodent model. The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was used in this study. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride staining, brain water content, perivascular aquaporin protein-4 (AQP4) localization, pericyte marker platelet-derived growth factor receptor β (PDGFRβ), and CBF velocity were evaluated at 24 h after MCAO/R and HDT treatment. In the rat model of MCAO/R, brain infarct volume and neurological deficit score were significantly alleviated in the -30° and -60° groups compared to those in the lying flat (0°) group. Compared with the 0° group, an increase in CBF velocity was detected in the -30° group through two-photon microscopy imaging at 24 h after MCAO/R. Compared with the SHAM group, a decrease in PDGFRβ was observed in both the MCAO/R and HDT treatment (-30°) groups. The integrated optical density of PDGFRβ was found to be higher in the HDT treatment (-30°) group than in the MCAO/R group. An impairment in perivascular AQP4 polarity and an increase in brain water content were observed after MCAO/R, which were not exacerbated by HDT treatment (-30°). Our findings suggest that HDT treatment at certain degrees may exert a neuroprotective effect after MCAO/R through improving CBF velocity and the protection of pericytes.

Abstract WP172: Advancing Age is a Predictor of Poor Collaterals

Introduction: Robust leptomeningeal collaterals protect the brain from ischemia, yet the determinants of poor collaterals have not been established. We aimed to identify predictors of poor collaterals in patients with large vessel occlusive stroke. Methods: Consecutive patients with large vessel occlusive stroke who underwent thrombectomy at 2 academic medical centers (derivation cohort/validation cohort) from 2012-2017 were included. Poor collaterals were defined as ≤50% filling on CT angiogram. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: demographics (age, sex, race), risk factors (hypertension, diabetes, atrial fibrillation, smoking), hemodynamics (blood pressure, cardiac output, troponin), metabolic (hyperglycemia, hyponatremia, uremia), hematologic (anemia, leukocytosis, thrombocytosis) and neuroimaging evidence of chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease. Results: Of the 248 total patients, poor collaterals were detected in 107 (43%). Mean age was 71±14y vs. 63±16y in patients with poor vs good collaterals, respectively (p<.001). There were 136 patients in the derivation cohort; 54 (48%) patients with poor collaterals. Multivariable modeling identified that older age (OR 1.8, p<.001), hyperglycemia (OR 2.4, p=.029) and white matter hyperintensities (WMH) (OR 6.1, p=.003) were independent predictors of poor collaterals in the derivation cohort. The validation cohort consisted of 136 patients; 53 (39%) had poor collaterals, of which older age (OR 1.4, p=.015), thrombocytosis (OR 24.0, p=.012), and WMH (OR 6.7, p=.018) were significant predictors of poor collaterals. Age and WMH were the only significant predictors of poor collaterals across the derivation and validation cohorts. When pooled the cohorts, older age (OR=1.5, p<.001), thrombocytosis (OR=7.6, p=.001) and WMH (OR=6.4, p<.001) were significant predictors of poor collaterals. Conclusions: We have identified that advanced age, WMH, and thrombocytosis are predictors of poor collaterals. Future studies to explore the effect of vascular aging on collateral therapeutics are indicated.

Abstract WP407: Function and Reactivity of Pial Collaterals In Vivo in Normotensive and Hypertensive Rats: Response to Ischemia and Reperfusion

Background: Collateral therapeutics is an emerging treatment for acute ischemic stroke. However, whether pial collaterals have tone in vivo and thus the ability to vasodilate is not clear. We investigated the function of pial collaterals in vivo during ischemia and reperfusion in normotensive and hypertensive rats that are known to have poor collaterals. We hypothesized that pial collaterals from spontaneously hypertensive rats (SHR) would have greater basal tone during ischemia and reperfusion than normotensive Wistar rats that could contribute to decreased collateral perfusion. Methods: A cranial window was performed in SHR (n=4) and Wistar (n=4) rats prior to remote middle cerebral artery occlusion (MCAo) under pentobarbital anesthesia. Video microscopy was used to measure changes in diameter of leptomeningeal anastomoses (LMAs) during MCAo for 2 hrs and 2 hrs reperfusion (Figure, top). After reperfusion, the brain surface was exposed to physiological saline solution with EDTA (67 mmol/L) to measure fully relaxed diameters and calculate basal tone. Blood pressure was measured via arterial catheter and animals were mechanically ventilated to control blood gases. Results: Blood pressure was significantly elevated in SHR vs. Wistar rats (157±9 vs. 107±7; p<0.01). LMAs (~15-20 μm diameters) had basal tone that was higher in SHR vs. Wistar (15.4±9% vs. 8.4±4.9%; n.s.). After 5 min MCAo, tone in LMAs from Wistar rats decreased to 2.7±1.5% but increased to 17.2±9.7% in SHR. Reperfusion caused vasoconstriction of LMAs from both groups and increased tone to 18.7±5.3% in Wistar and to 29.5±9.7% in SHR (p<0.01 vs. basal for both; Figure, bottom). Conclusions: These data demonstrate functional pial collaterals in normotensive and hypertensive rats. While increased tone of LMAs during MCAo in SHR could limit perfusion to the penumbra, vasoconstriction of LMAs from both groups suggests therapeutic intervention to increase diameter and salvage at risk tissue is possible.

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3 absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

Cerebral collateral circulation in experimental ischemic stroke.

Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. Experimental stroke models may play a unique role in understanding the adaptive response of cerebral collaterals during ischemia and their potential for therapeutic modulation. The systematic assessment of collateral perfusion in experimental stroke models may be used as a “stratification factor” in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals in stroke models may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in term of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute (even pre-hospital) phase of ischemic stroke, prior to recanalization therapies.

Transient Aortic Occlusion Augments Collateral Blood Flow and Reduces Mortality During Severe Ischemia due to Proximal Middle Cerebral Artery Occlusion.

Cerebral collateral circulation provides alternative vascular routes for blood to reach ischemic tissues during stroke. Collateral therapeutics attempt to augment flow through these collateral channels to reduce ischemia and brain damage during acute ischemic stroke. Transient aortic occlusion (TAO) has pre-clinical data suggesting that it can augment collateral blood flow and clinical data suggesting a benefit for patients with moderate cortical strokes. By diverting blood from the periphery towards the cerebral circulation, TAO has the potential to augment primary collateral flow at the circle of Willis and thereby improve outcome even during large, hemispheric strokes. Using proximal middle and anterior cerebral artery occlusion in rats, we demonstrate that TAO reduces mortality and improves collateral blood flow in severely ischemic animals. As such, TAO may be an effective therapy to reduce early mortality during severe ischemia associated with proximal occlusions.

Neuroprotectives in Acute Ischemic Stroke, Hope or Hype?

Stroke is a significant public health burden which absolutely requires more effective therapies. The approved treatment options for stroke including tissue plasminogen activators, antiplatelet agents and anticoagulants mainly bear antithrombotic effects. Meanwhile, evolving investigational approaches such as collateral therapeutics and neuroprotective agents has thus far been attempted with equivocal effects on stroke outcome. The basic structural and ultrastructural changes following acute ischemic stroke should be well-considered when trying to target oxidative stress and cell death pathways using neuroprotective agents. Clearly, the positive results of preclinical studies on neuroprotectives and collateral therapeutics in stroke do not necessarily translate to the true clinical benefits of these agents. As such, several large advance-phased trials have already failed to prove so. On the other hand, controversial results in clinical setting should not discourage further research endeavors on the same. Besides, the concurrent use of flow augmentation and neuroprotectives may serve further clinical benefits. Based on the available evidence, it appears that optimization of preclinical studies and further well-designed prospective clinical trials let neuroprotection possibly find its position in stroke management. The present paper discusses key preclinical and clinical studies on neuroprotectives towards improved outcome in acute ischemic stroke.

Cerebral collaterals and collateral therapeutics for acute ischemic stroke.

Cerebral collaterals are vascular redundancies in the cerebral circulation that can partially maintain blood flow to ischemic tissue when primary conduits are blocked. After occlusion of a cerebral artery, anastomoses connecting the distal segments of the MCA with distal branches of the ACA and PCA (known as leptomeningeal or pial collaterals) allow for partially maintained blood flow in the ischemic penumbra and delay or prevent cell death. However, collateral circulation varies dramatically between individuals, and collateral extent is significant predictor of stroke severity and recanalization rate. Collateral therapeutics attempt to harness these vascular redundancies by enhancing blood flow through pial collaterals to reduce ischemia and brain damage after cerebral arterial occlusion. While therapies to enhance collateral flow remain relatively nascent neuroprotective strategies, experimental therapies including inhaled NO, transient suprarenal aortic occlusion, and electrical stimulation of the parasympathetic sphenopalatine ganglion show promise as collateral therapeutics with the potential to improve treatment of acute ischemic stroke.

Cerebral collateral flow defines topography and evolution of molecular penumbra in experimental ischemic stroke

Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.

Augmenting Collateral Blood Flow during Ischemic Stroke via Transient Aortic Occlusion

Collateral circulation provides an alternative route for blood flow to reach ischemic tissue during a stroke. Blood flow through the cerebral collaterals is a critical predictor of clinical prognosis after stroke and response to recanalization, but data on collateral dynamics and collateral therapeutics are lacking. Here, we investigate the efficacy of a novel approach to collateral blood flow augmentation to increase collateral circulation by optically recording blood flow in leptomeningeal collaterals in a clinically relevant model of ischemic stroke. Using high-resolution laser speckle contrast imaging (LSCI) during thromboembolic middle cerebral artery occlusion (MCAo), we demonstrate that transiently diverting blood flow from peripheral circulation towards the brain via intra-aortic catheter and balloon induces persistent increases in blood flow through anastomoses between the anterior and middle cerebral arteries. Increased collateral flow restores blood flow in the distal middle cerebral artery segments to baseline levels during aortic occlusion and persists for over 1 hour after removal of the aortic balloon. Given the importance of collateral circulation in predicting stroke outcome and response to treatment, and the potential of collateral flow augmentation as an adjuvant or stand-alone therapy for acute ischemic stroke, this data provide support for further development and translation of collateral therapeutics including transient aortic occlusion.

Dynamic change of collateral flow varying with distribution of regional blood flow in acute ischemic rat cortex

Cerebral blood flow (CBF) is critical for the maintenance of cerebral function by guaranteed constant oxygen and glucose supply to brain. Collateral channels (CCs) are recruited to provide alternatives to CBF to ischemic regions once the primary vessel is occluded during ischemic stroke. However, the knowledge of the relationship between dynamic evolution of collateral flow and the distribution of regional blood flow remains limited. In this study, laser speckle imaging was used to assess dynamic changes of CCs and regional blood flow in a rat cortex with permanent middle cerebral artery occlusion (MCAo). We found that CCs immediately provided blood flow to ischemic territories after MCAo. More importantly, there were three kinds of dynamic changes of CCs during acute stroke: persistent CC, impermanent CC, and transient CC, respectively, related to different distributions of regional blood flow. Although there was the possible occurrence of peri-infarct depolarization (PID) during ischemia, there was no obvious significance about the onset time and duration of CCs between rats with and without PID. These results suggest that the initial arising of CCs does not ensure their persistence, and that collateral flow could be varied with distribution of regional blood flow in acute ischemic stroke, which may facilitate the understanding of collateral recruitment and promote the development of collateral therapeutics in the future.

Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke

Intracranial collaterals provide residual blood flow to penumbral tissue in acute ischemic stroke and contribute to infarct size variability in humans. In the present study, hemodynamic monitoring of the borderzone territory between the leptomeningeal branches of middle cerebral artery and anterior cerebral artery was compared to lateral middle cerebral artery territory, during common carotid artery occlusion and middle cerebral artery occlusion in rats. The functional performance of intracranial collaterals, shown by perfusion deficit in the territory of leptomeningeal branches either during common carotid artery occlusion or middle cerebral artery occlusion, showed significant variability among animals and consistently predicted infarct size and functional deficit. Our findings indicate that leptomeningeal collateral flow is a strong predictor of stroke severity in rats, similarly to humans. Monitoring of collateral blood flow in experimental stroke is essential for reducing variability in neuroprotection studies and accelerating the development of collateral therapeutics.

Reperfusion for acute ischemic stroke: arterial revascularization and collateral therapeutics

Reperfusion of the ischemic territory forms the basis of most acute stroke treatments. This overview of the literature relating to reperfusion in acute ischemic stroke published within the last year provides a snapshot of a rapidly evolving aspect of cerebrovascular disease. Arterial revascularization from systemic thrombolysis to combination endovascular procedures to achieve recanalization has proliferated. Stroke imaging continues to discern features of critical pathophysiology that may influence tissue fate and clinical outcome. Balancing the risk of hemorrhagic transformation against the therapeutic aim to salvage the ischemic penumbra remains a formidable challenge. Collateral therapeutics that enhance perfusion outside the ischemic core present novel dimension to acute stroke therapy, focused on ischemia and not just the clot or plaque. These timely findings illustrate the essential role of reperfusion in acute stroke, delineating aspects of arterial revascularization and collateral therapeutics to be refined in coming years.

Venous Hemodynamics May Enhance Collateral Perfusion and the Fibrinolytic Milieu in Paradoxical Embolism

To the Editor: Paradoxical embolism via right-to-left shunts (RLS) has rapidly evolved into an area of intense research in stroke and migraine. Increasing attention focuses on distinguishing anatomic features of a patent foramen ovale (PFO) visualized by transesophageal echocardiography (TEE) from functional aspects (ie, shunts) that allow clots to pass from venous to arterial circuits, thereby circumnavigating typical filtration in the lungs. TEE and transcranial Doppler (TCD) microbubble injection techniques may detect shunting at rest or with Valsalva maneuver to accentuate venous pressures, yet thromboemboli are rarely noted. Intense speculation, however, has centered on clot composition and potential response to fibrinolytics despite that only a few dozen clots causing strokes in humans have ever been analyzed. Kimura et al provide fascinating data demonstrating a link between RLS and dramatic response to fibrinolytics in acute stroke (OR, 5.9; 95% CI, 1.3 to …

Of Mice and Men: Essential Considerations in the Translation of Collateral Therapeutics

To the Editor: Shin and colleagues detail an elegant study of collateral perfusion in the ischemic penumbra of mice treated with induced hypertension after distal middle cerebral artery occlusion (MCAO).1 Using optical imaging techniques, they demonstrate that early augmentation of systemic blood pressure with phenylephrine after MCAO improves collateral flow from ipsilateral leptomeningeal branches of the anterior and posterior cerebral arteries. Such collateral perfusion is noted to markedly improve cerebral blood flow (CBF) in penumbra and core, with associated enhancement of oxygenation and cerebral metabolic rate of oxygen in these ischemic regions. After prompt reversal of distal MCAO, infarct size is reduced by induced hypertension in concentric fashion around a focus emanating from the site of distal MCAO. There are subtle yet critical details embedded in this sophisticated cerebrovascular pathophysiology experiment that must be considered regarding the potential of induced hypertension and other therapeutic approaches using collateral perfusion in acute ischemic stroke patients.2 Changes …

Response to Letter by Liebeskind

Response: We thank Dr Liebeskind for his interest in our study and appreciate his comments underscoring the complexity of enhancing perfusion to improve outcome in metastable ischemic brain tissue. We see merit in most of his comments and recognize the contributions he has made to collateral therapeutics in acutely ischemic brain. We would like to take this opportunity to clarify what may have been lost in translation. Dr Liebeskind observes that ischemic core was situated only microns away from the penumbra in our model, and considers this a marked discrepancy with human stroke. The calculation he makes underestimates considerably the values we obtained. To estimate salvageable penumbra in our model, we …

FGF-4 gene therapy GENERX--Collateral Therapeutics.

Collateral Therapeutics and Schering AG in Germany are developing a gene therapy product, GENERX for coronary artery disease. Based on the terms of the agreement, Schering or its affliates will be responsible for conducting and financing phase II/III clinical trials which are currently underway in the US and Europe. In particular, Berlex Labs (the US subsidiary of Schering AG), is involved in developing the gene therapy in the US. GENERX is an angiogenic gene therapy which triggers the production of a protein that stimulates new blood vessel growth providing an alternative route for blood to bypass clogged and blocked arteries in the heart. GENERX involves a one-time, non-surgical delivery of an adenovirus vector containing the human fibroblast growth factor-4 (FGF-4) into coronary arteries via a standard catheter. The FGF-4 gene was licensed from New York University. Collateral Therapeutics has been granted a US patent for "gene transfer-mediated angiogenesis therapy" for the nonsurgical administration of angiogenic genes for coronary and peripheral vascular disease. The patented technology has been licensed from the University of California. Collateral and Berlex have initiated pivotal phase IIb/III trials with GENERX in the US and Europe. The US-based study will evaluate the safety and efficacy of GENERX in patients with stable exertional angina due to coronary artery disease. The European-based study will evaluate patients with advanced coronary artery disease who are not considered candidates for interventions such as angioplasty and bypass surgery and/or patients who are unlikely to have positive outcomes from such interventions. Both studies, of a multicentre, randomised, double-blind and placebo-controlled design, will evaluate 2 dose levels of GENERX which will be non-surgically administered to the heart via intracoronary infusion through a standard cardiac catheter. Collateral also plans to develop a non-surgical gene therapy product using the FGF-4 gene for the treatment of patients with heart failure. In a blinded placebo-controlled study in a pig model of pacing-induced heart failure, intracoronary delivery of human FGF-4 expressed in an adenovirus vector showed significant improvement in regional cardiac function and a reduction in the size of the heart over a 3-week study period. If these results translated favourably to humans, FGF-4 gene therapy may be a therapeutic option for patients with dilated heart failure. Collateral Therapeutics has also announced a research collaboration with Targeted Genetics on the use of viral vectors to deliver therapeutic genes in cardiovascular disease. Under the terms of the agreement, Targeted Genetics and Collateral Therapeutics each have the option to collaborate further to use Targeted Genetics' recombinant adeno-associated viral vector to treat congestive heart failure. In such an event, Targeted Genetics would be responsible for constructing and manufacturing the vector, and Collateral Therapeutics will fund the costs of future collaboration. Either party may terminate this agreement at any time upon 30 days prior written notice.

Intracoronary gene transfer of fibroblast growth factor in experimental and clinical myocardial ischemia

An animal model of stress-induced regional myocardial ischemia was used to test the hypothesis that intracoronary delivery of an adenovirus encoding fibroblast growth factor Type 5 (FGF5) would result in improved blood flow, function and neovascularization in the ischemic region of the heart. These data indicated that this approach could be used safely and effectively in resolving regional myocardial ischemia in the ameroid model. Additional unpublished studies confirmed that a similar effect was achievable through use of other angiogenic transgenes, including FGF Type 4 (FGF4). The published studies using direct intracoronary delivery of adenovirus vectors to the heart is reviewed, with a focus on safety and efficacy. A multicenter Phase 1/Phase 2 clinical trial of intracoronary delivery of FGF4 in patients with angina pectoris was initiated under joint sponsorship of Collateral Therapeutics, Incorporated, Berlex Biosciences and Schering AG. Results of this trial are reviewed. The results of this blinded and randomized clinical trial provided data supporting the initiation of two large scale pivotal clinical trials — in the European Union and the US — of intracoronary delivery of adenovirus encoding FGF4 in treating patients with angina.

Seeing the Duties to All

As biotech revolution hits full stride, one is as likely to find stories on emerging medical technologies in business section as in science section. As New York Times notes, reporting case of academic researcher Kirk Hammond, also founder of company Collateral Therapeutics, With biomedical revolution in full swing, academic scientists who lack industry ties are as rare as giant pandas in wild.[1] Conflicts of interest for clinical researchers have long been seen as an issue in bioethics. Yet bioethicists themselves negotiate with temptations as potent as those faced by research scientists. We are funded not only by universities, but by private donors directly or only once removed from very industries we assess. This article reflects on this emerging problem: conflict faced by a bioethicist who participates as a consultant in research, often in private sector and often on new biotechnology or pharmaceuticals. I will make two claims about conflicts of interest in field of bioethics. The first is that there is and should be a conflict of interest whenever we take a realistic look at any new technology. It is in nature of bioethics that contention is a part of moral reflection, that competing moral appeals call upon our loyalty. Only by a stark appraisal of deep calls to conscience that participation in bioethics consultancy ought to provide can we understand depths of potential breaches of ethics in work. The second claim is that to focus question posed by conflicts of interest on rules about finances is a diversion, a necessary but ultimately simplistic account of temptations of power and influence that are part of work of bioethicist. I hope here to raise some preliminary questions for our further exploration.[2] It is my contention that questions that should animate us are not normative or regulatory ones, but epistemic and ontological ones: How can one know what one needs to know to consult on a new technology? Who does one become by taking part in this consultancy? The Duty to Third To be observant as a consultant is to notice conflict. When bioethicists are invited to consult on biotechnology, their role is to introduce social--implications for future, history of past abuses, and present considerations of justice. Conflict is only meaningful possibility for debate. Every interaction of abstract principles occurs within a narrative context, every boardroom discussion takes place within a larger social and political frame--the marketplace, clinic, public square--and it is role of ethicist to pull narrative frame from private view within institution to larger world that surrounds institution, a world of obligation, of suffering, of injustice, and of potential. It is this ability, this role of narrative construction, that allows for reflection and assessment. It is made possible by presence of what Levinas calls the third, witness to interaction of self and constantly calling other that interrupts self.[3] Because it is presence of third that makes judgment--and hence justice--possible, it is important to see problem of conflict as a radical opportunity, not an avoidable mistake. Only in frank confrontation with an alternative view is it possible to understand total alterity of another and need to include this alternative in our deliberations. Because narrative of poor, uninsured, or marginalized might not be represented at table, ethicist is entrusted with their story. The bioethicist might also hear from a range of more particular communities--disease groups, disabilities groups, patient advocacy groups. In all of this, it is being alive to double-horned dilemma that is useful. We hold things in tension--the reasonableness of a marketplace, realpolitik of private financing, nature of social constraints of our health care funding, and aspirations of justice. …