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Our awards are framed into the 4 models or paths to innovation as described by Boni and Joseph, and published in JCB previously in two companion articles, c. f. JCB Vol. 24, No. 4 (2020); “Aligning the Corporation for Transformative Innovation: Introducing Dashboard 2.0”, pp 14-22, &“Four Models for Corporate Transformative, Open Innovation”, pp. 23-31. The 4 models that we categorized can be summarized: 1) Direct Entrepreneurship; 2) Consortia/Alliances – open innovation partnerships or alignments with Startups & Emerging Companies; 3) External Accelerators; and, 4) Corporate Accelerators.

This introductory article summarizes our basis for recognition of innovative companies (past, present and emerging) in our industry, and summarizes the criterion that we are using to evaluate those organizations selected for contributing to innovation in the life sciences industry. We also develop and list both industry leaders, both pioneers and current, who we selected as members of the JCB Innovators Hall of Fame - 2021.

This article summarizes our intent and basis for recognition of innovators in our industry, including the criterion that we are using for those organizations selected. Our focus for this year is largely on the Biopharma segment, because of Covid-19 and the positive and significant impact that our industry has made in that regard. We focus on companies across the life cycle from startups ranging to the large multi-national pharma companies.

This issue provides a perspective on emerging, transformative technologies that promise to create innovations that are intended to provide solutions for significant problems in the biopharma and broader healthcare market. Many of these technologies have been evolving over the years, but remain in their early development stages technologically. As with most transformative innovations, they come with a host of lengthy and expensive challenges associated with development and validation. And, implementation of transformative business models that are at least as challenging as commercializing the technologies themselves.

The Small Business Innovation Research (SBIR) program was created to stimulate technological innovation and business development at early stage companies in the United States. In its 21-year history, the program has channeled over $35 billion of public funds to private businesses in the form of approximately 137,000 grants. However, the question of whether SBIR funding effectively spurs new innovation and promotes commercialization remains controversial. Here, we review efforts to answer this question and perform an independent analysis to evaluate the success of the SBIR program in a representative high technology industry. To do this, we systematically analyzed publicly available data for biotechnology companies based in Pennsylvania that received SBIR funding through the Department of Health and Human Services (HHS) between 1983 and 2014. Our analysis did not find any clear relationships between the amount of SBIR funding received and acquisition of private funding or intellectual property. However, higher SBIR funding rates were associated with current operating status and number of publications, indicating that these additional grants do support commercial operations and the advancement of scientific knowledge. Taken together, our study provides a comprehensive overview of the SBIR program for Pennsylvania biotechnology companies and reveals myriad uses for federal funding to support company development and foster innovation for the public good. These findings underscore the complexity of evaluating the SBIR program and the need for increased standardization and centralization of outcomes data for this large and growing federal program.

These laws have passed rather quickly in Colorado, Michigan, Missouri, Louisiana and Arizona with legislators in other states promising to introduce similar bills in 2015. Basically what these bills in one form or another propose to do is to give seriously or critically ill patients the right to access medications that have not been approved by the FDA and have only been through Phase I clinical trials. While there are slight variations from state-to-state, common language amongst the bills stipulates that once a patient has exhausted all other therapeutic options, the patient and his/ her doctor can approach a BioPharma firm for permission to gain access to a drug even though it has only been through Phase I clinical trials. The major operational and ethical caveat in all this is that Phase I clinical studies only involve perhaps 20-50 patients, usually normal healthy volunteers, and is really focused on determining if the potential therapeutic is safe and tolerated: Not does it cure or treat a disease. In essence, these laws aim to hasten access to hopefully lifesaving but unapproved drugs by completely removing oversight by the FDA. This would all be a good for society and terminally ill patients if the driving force of increased accessibility was a real problem but it isn’t. The FDA already has in place an “expanded access” or “compassionate use” program for granting access to unapproved therapies in patients with exceptional medical needs.

Our hypothesis is that PGs released within the kidney play a role in the modulation of kidney production of Ep. PGs release probably at medullary and/or cortical sites following erythropoietic stimuli such as hypoxic hypoxia, anemic hypoxia, and ischemic hypoxia induced by renal artery constriction increase kidney production of Ep. PGs which are released probably activate a renal cortical adenylate cyclase thereby enhancing the production of intracellular cAMP. This initiates the cascade of events resulting in the production and/or secretion of Ep by the kidney. The endoperoxide analogs and PGE2 have been found to produce a dose-related and Ep-dependent increase in radioiron incorporation into newly formed red blood cells of exhypoxic polycythemic mice. Indomethacin, a potent PG cyclo-oxygenase inhibitior, attenuates Ep production and the appearance of PGE in the renal venous effluent of animals exposed to hypoxic hypoxia and renal artery constriction. Arachidonic acid (C20:4) and PGE2 infusion into the posthypoxic isolated perfused dog kidney produced a significant elevation in Ep titers in the perfusate. The increase in Ep production caused by arachidonate is blocked by indomethacin. It has been previously reported that PGs of the E series stimulate cAMP formation in several tissues. We have found that not only are renal cortical cAMP levels significantly elevated in rats following exposure to hypobaric hypoxia but that dibutyryl cAMP administration produces an increase in hematocrit and circulating red cell mass in normal mice. Our data thus far strongly support the hypothesis that the renal PGs and the cyclic nucleotides are intimately involved in the pharmacologic and/or pathophysiologic control of Ep production. Further work is necessary to determine whether the PGs and cyclic nucleotides are involved in the day-to-day control of Ep production by the mammalian kidney.

L-681,176, an inhibitor of angiotensin converting enzyme was found in the culture filtrate of Streptomyces sp. MA 5143. The I50 of the crystalline inhibitor is about 1.3 micrograms/ml and the inhibition is reversed by zinc sulfate. In rats, L-681,176 exhibits a dose-related inhibition of the pressor response to angiotensin I with an ID50 of 142 mg/kg when administered intravenously. The structure of L-681,176 is similar to that of marasmine but lacking one carboxyl group. The maximum yield of L-681,176 occurs after three to four days growth at 28 degrees C.

SummaryRenal artery constriction (RAC) to 30% of normal flow for 12 hr in the unilaterally nephrectomized dog produced a marked increase in both erythropoi-etin titers and prostaglandin E (PGE) levels in the blood. In dogs pretreated prior to RAC with indomethacin, a potent inhibitor of prostaglandin synthetase, there was no significant increase in either PGE or eryth-ropoietin levels as compared to zero-time control values. These data suggested an involvement of renal PGE in the generation of erythropoietin following RAC.The authors gratefully acknowledge the excellent technical assistance of Mr. Jesse Brookins, Ms. Patricia Dargon, Mr. Rene Stiaes, and Mrs. Jacqueline Frailey.

An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.

The automation of an isolated atria assay is described. Data acquisition, operation of the strip chart recorder, data reduction and manipulation and generation of notebook pages showing final EC50's, dose-ratios and local pA2's has been completely automated. The data are acquired via a SYM-1 (6502 CPU) 8-bit single board computer running an assembly language program stored on an EPROM chip. The data from a physiological recorder system are stored by the SYM-1 and, at the conclusion of the experiment, transmitted to a DEC MINC-11 microminicomputer running a sequence of programs in BASIC for the mathematical manipulation of the data and the automatic generation of lab notebook pages. The automated system totally eliminates hand transcription of data, manual plotting of curves and mathematical errors.

The central antihypertensive properties of four γ-aminobutyric acid (GABA) analogs were characterized in anesthetized cats with implanted intracerebroventricular cannulae. An intracerebroventricular infusion (ICV) of muscimol, 0.1-0.5 μg/min (total dose: 1–5 μg ICV), substantially reduced mean arterial pressure and slightly reduced heart rate. The compound was not hypotensive at 5 μg IV (total dose) and only slightly hypotensive after an intracisternal injection (5 μg). Kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one) and baclofen were also hypotensive following an intracerebroventricular infusion, but they were less active than muscimol. GABA, at 15–150 μg/min ICV (total dose, 150–1500 μg ICV), was not hypotensive by itself and unlike muscimol its activity was not enhanced in cats pretreated with nipecotic acid, an uptake inhibitor of GABA. The ability of muscimol to interfere with baroreceptor reflexes was considered in experiments in which reflex vasoconstrictor (carotid occlusion) and reflex vasodilatation (acute elevation in mean arterial pressure with norepinephrine) was measured in the perfused hindlimb of cats previously prepared with intracerebroventricular cannulae. Muscimol significantly attenuated the response to bilateral carotid occlusion and completely abolished reflex vasodilatation. These results suggest that GABA agonists and analogs may regulate blood pressure centrally and, through an interaction with the central nervous system, may attenuate baroreceptor reflexes.

The central antihypertensive properties of four gamma-aminobutyric acid (GABA) analogs were characterized in anesthetized cats with implanted intracerebroventricular cannulae. An intracerebroventricular infusion (icv) of muscimol, 0.1--0.5 microgram/min (total dose: 1--5 micrograms, icv), substantially reduced mean arterial pressure and slightly reduced heart rate. The compound was not hypotensive at 5 micrograms, iv (total dose) and only slightly hypotensive after an intracisternal injection (5 micrograms). Kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one) and baclofen were also hypotensive following an intracerebroventricular infusion, but they were less active than muscimol. GABA, at 15--150 micrograms/min, icv (total dose, 150--1500 micrograms, icv), was not hypotensive by itself and unlike muscimol its activity was not enhanced in cats pretreated with nipecotic acid, an uptake inhibitor of GABA. The ability of muscimol to interfere with baroreceptor reflexes was considered in experiments in which reflex vasoconstrictor (carotid occlusion) and reflex vasodilatation (acute elevation in mean arterial pressure with norepinephrine) was measured in the perfused hindlimb of cats previously prepared with intracerebroventricular cannulae. Muscimol significantly attenuated the response to bilateral carotid occlusion and completely abolished reflex vasodilatation. The results suggest that GABA agonists and analogs may regulate blood pressure centrally and, through an interaction with the central nervous system, may attenuate baroreceptor reflexes.

1. 1. Zonal rotors which do not require rotating-seal assemblies were tested and employed for quantitative cell fractionations in sucrose density gradients. The design and operation of these rotors represents a departure from other zonal rotors presently in use. These rotors may be either statically or dynamically loaded but are always statically unloaded following deceleration. During deceleration, the density gradient within the rotor undergoes a gradual reorientation from a radial to a vertical distribution. Gradients and separated particles are then pumped from the floor of the rotor. 2. 2. The reorienting gradient rotors were used to fractionate liver homogenates and the resulting distribution of cell particles in the collected gradient examined and identified by a combination of microscopic and biochemical methods. Several interesting and unusual features of reorienting gradient zonal rotors are discussed.

Two synthetic approaches were used to prepare, in chirally pure form, the beta-adrenoceptor antagonist 9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene (1a). One of these employed the oxazolidine (S)-6 generated from D-mannitol, while the other utilized (S)-[[(trifluoromethanesulfonyl)oxy]methyl]oxirane (4) as the chiral three-carbon fragment. This latter synthesis was designed to incorporate the amino function in the last step. In vitro, a beta 2 selectivity of only 2.2 was observed for 1a. The example, (S)-9-[[3-(tert-amylamino)-2-hydroxypropyl]oximino]fluorene (1b), was also prepared and found to be selective for the beta 1 receptor by a factor of 2.5. In contrast to other beta-adrenoceptor antagonists, the enantiomers of 1a exhibited no chiral preference; i.e., (S)-1a and (R)-1a possessed a similar order of beta-adrenoceptor antagonistic activity.

Erythropoietin (Ep) is well known to be the primary regulator of erythropoiesis; its major effect is on the erythroid committed stem cells, causing their differentiation into the heme-synthesizing nucleated erythroid cell compartment.1–4 As outlined by Stohlman4 the differentiated erythroid cell compartment is not self-sustaining and must be supported by an influx of cells from a stem cell precursor compartment. Stohlman4 has suggested that erythropoietin not only initiates but also governs the rate of hemoglobin synthesis and the rate of maturation of erythroid cells. Bottomley5 found that Ep stimulated the rate-limiting enzyme δ-aminolevulinic acid synthetase, but not heme synthetase, in rabbit bone marrow erythroid cells. Early work has demonstrated that high sustained dosages of erythropoietin are capable of triggering the early release of reticulocytes from the bone marrow.6,7 It is the primary purpose of this chapter to consider pharmacological agents, some of which are naturally occurring in mammalian species, in modulating erythropoiesis in the stem cell compartment either alone or in concert with erythropoietin.

The exact mechanism of action of angiotensin converting enzyme (ACE) inhibitors in reducing blood pressure is not known, although inhibition of angiotensin II formation is the generally accepted mechanism. Experiments were performed in two models of experimental hypertension to determine whether or not inhibition of the pressor response to angiotensin I, 300 ng/kg. i.v., would correlate with the antihypertensive response to single oral doses of N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-Ala-L-Pro(MK-421), a new ACE inhibitor. Captopril, given a single oral dose, was studied in spontaneously hypertensive rats (SHR) for comparative purposes. In SHR, MK-421 at 0.1–3 mg/kg p.o. and captopril at 0.1–3 mg/kg p.o. were approximately equipotent with regard to inhibiting the pressor response to angiotensin I (relative potency = 1.7; 95% C.I. = 0.7–4.5). The magnitude of ACE inhibition and onset of action were similar with both agents, but MK-421 had a longer duration of action. The decrement in systolic pressure following each ACE inhibitor consisted of an initial decrease in blood pressure corresponding to the maximal inhibition of angiotensin I pressor response and a secondary fall in blood pressure which was evident 5–6 h after treatment. At this time, the inhibition of the pressor response to angiotensin I was minimal. Thus, the time course for blockade of angiotensin I and the blood pressure reduction did not correspond. The dose-response regression lines for the antihypertensive effect of each inhibitor, unlike those for ACE inhibition, were flat. The potency ratio computed on the basis of the maximum fall in blood pressure over 6 h revealed that MK-421 was 11.5 times (P < 0.05) more potent than captopril. In 2-kidney Grollman renal hypertensive rats (RHR), MK-421 at 0.3–10 mg/kg p.o. inhibited the pressor response to angiotensin I by 65–95%, but produced significant decrement in blood pressure only at 10 mg/kg p.o. The finding tha MK-421 was more potent than captopril in lowering blood pressure in SHR, yet equally active in its ability to block angiotensin I pressor response, suggests that a mechanism(s) other than inhibition of plasma ACE is involved in the decrease in blood pressure in SHR. In RHR, MK-421 at 3.0 mg/kg p.o. blocked angiotensin I pressor response by greater than 90% yet blood pressure was not reduced. However, a higher dose which produced a similar degree of blockade was associated with a significant decrease in blood pressure.

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.

The effect of albuterol, a potent beta2-adrenergic agonist, on kidney production of erythropoietin (Ep) was studied. Its effects on erythroid colony (CFU-E) formation in vitro in rabbit bone marrow cultures were also assessed. Albuterol produced a significant increase in plasma Ep levels in conscious rabbits following 7 h intravenous infusion (50 (microgram/kg)/min). This effect was blocked by pretreatment of the rabbits with butoxamine (5 mg/kg ip), a potent beta2-adrenergic blocker. Albuterol in doses of 10(-10) to 10(-8) M in combination with Ep was also found to produce a significant increase in the numbers of CFU-E in the plasma clot culture system of rabbit bone marrow. This effect was blocked completely by DL-propranolol (10(-8) M) and by butoxamine (10(-8) M). The data presented suggest that albuterol, a potent activator of beta2-adrenergic receptors, increases kidney production of Ep in vivo and also produces a direct effect in combination with Ep on the proliferation of the erythroid progenitor cell compartment.

Direct comparison of drug interaction with intraocular relative to extraocular beta-adrenergic receptors was used to test the hypothesis that the receptors in ocular tissues are of the beta 2-subtype. Potencies for the displacement of 3H-dihydroalprenolol radioligand binding to membranes obtained from rabbit-iris ciliary bodies by beta-adrenoceptor agonists was in the order: isoproterenol greater than or equal to epinephrine greater than salbutamol greater than terbutaline greater than tazolol greater than norepinephrine. Similar radioligand displacement by beta-adrenoceptor antagonists was in the order of potency: alprenolol greater than or equal to bupranolol = oxprenolol = timolol = propranolol greater than ICI 118,551 = IPS 339 much greater than betaxolol greater than metoprolol. Finally, for the above beta-adrenoceptor antagonists, a highly significant correlation was obtained for displacement of radioligand to ocular tissues (pKi values) relative to antagonism (pA2 values) of isoproterenol-induced guinea-pig tracheal relaxation but not guinea-pig atrial chronotropic effects. Consequently, the above three observations reinforce the notion that rabbit-iris ciliary bodies contain beta-adrenergic receptors predominantly of the beta 2-subtype.

Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing 3H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of alpha-chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial beta-adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular beta-adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular beta-adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular beta-adrenergic receptors showing relatively poor stereoselectively.