Russell J. Howard is an Australian-born executive, entrepreneur and scientist. He was a pioneer in the fields of molecular parasitology, especially malaria,[2][3][4][5][6] and in leading the commercialisation of one of the most important methods used widely today in molecular biology today called “DNA shuffling" or "Molecular breeding",[7] a form of "Directed evolution".
His contributions to malaria research over an 18-year period began in Australia at the Walter and Eliza Hall Institute of Medical Research, then continued as a tenured Principal Investigator at the National Institutes of Health (NIH) in Bethesda, MD, USA, and continued at the biotechnology companies DNAX (now Schering-Plough Biopharma) and Affymax in California. Thirteen years of his group's malaria research on antigenic variation in malaria[2][3][4][5][6][8][9][10][11][12][13][14][15][16][17][18] culminated in the first molecular cloning of the malarial antigen PfEMP1,[19] a parasite protein that this human malaria parasite expresses on the surface of malaria-infected red cells[4][5][20] This antigen represents critical biological functions for the parasite including immune evasion and adherence to microvascular endothelial cells.[21] During this time Howard served on the World Health Organization's Special Program for Research and Training in Tropical Diseases and the USAID program for research and vaccine development in malaria.
While Howard was President and Scientific Director at Affymax Research Institute, Willem 'Pim' Stemmer[22] conceived and developed DNA shuffling Technology.[7] This revolutionary technology for improving the expressed phenotype of genes, pathways, plasmids, viruses and genomes gave birth to the creation and spinout of Maxygen Inc.[23] where Howard was CEO for 12 years (1997-2009).
He took the company public in 1999[24] and led its growth with 10's of corporate partnerships and technology application programs that led ultimately to the development and commercialisation worldwide of 10's of Life Science products in diverse fields. Maxygen exploited DNA Shuffling technology across the entire Life Sciences spectrum, creating new companies dedicated to Agricultural Products (Verdia[25]) and Industrial Chemical opportunities (Codexis[26]) as well as a Protein Pharmaceuticals Business (Perseid[27]).
In 2008, Howard left Maxygen to found Oakbio Inc. in 2009. He remains Chairman of Oakbio Inc. (doing business as NovoNutrients Inc.), in Sunnyvale, California, USA. NovoNutrients uses proprietary microbes for CO2 capture from industrial processes. Industrial CO2 emissions are used as sole carbon source and H 2 gas as sole energy source to manufacture bacterial biomass, or single cell protein, a source of high quality protein for aquaculture and in future, for human foods .
Upon taking up residence in 2012 in Sydney, Australia, Howard became Executive Chairman of NeuClone Pty. Ltd., a clinical stage biotechnology company dedicated to development of biosimilars of monoclonal antibody drugs.
In 2013 Howard joined Prima Biomed Pty. Ltd., based in Sydney, Berlin and Paris, later renamed Immutep Pty. Ltd., as Non-Executive Director. In 2017 he took the role of Non-Executive Chairman and continues today in this role. Immutep develops novel immuno-oncology and autoimmune drugs based on its LAG3 patent estate.
Howard has published over 145 scientific publications in refereed journals and is an inventor on nine issued patents.
Education
Howard graduated from Box Hill High School in Melbourne, Australia and later majored in Chemistry and Biochemistry at the University of Melbourne, culminating in a PhD in 1975 where he studied the carbohydrate and central metabolism of Caulerpa simpliciuscula, a marine green alga.[30]
Employment
He spent his first postdoctoral studies from 1976 to 1979 at the Immunoparasitology Laboratory at the Walter & Eliza Hall Institute in Melbourne, with frequent visits and collaborative work on sialic acids at the Biochemisches Institut at Christian Albrechts Universitat in Kiel, Germany. He started working as a Research Associate in the Malaria Section of the National Institutes of Health in Bethesda, Maryland before earning his tenure in the same institution in 1987. From 1988 to 1992, he worked at the Laboratory of Infectious Diseases of the DNAX Research Institute of Molecular and Cellular Biology in Palo Alto, California, USA, with dual roles, studying cytokine genes for Schering Plough, the parent organisation of DNAX Research Institute, and leading his Infectious Diseases laboratory there on malaria work funded by DNAX and USAID.[31]
In 1994, he was named President and Scientific Director of Affymax, Inc. where he managed teams working on small molecule drug lead discovery using combinatorial chemistry and high throughput target screening. His independent malaria work continued at Affymax with support from USAID and Affymax, leading to cloning of the PfEMP1 gene while at Affymax.[19] After Affymax was purchased by GlaxoWellcome, Howard led technology transfer and interchange in combinatorial chemistry, drug discovery and optimisation between Affymax and GlaxoWellcome worldwide. During this time, Molecular breeding or DNA shuffling Technology was conceived[7] and the nascent company Maxygen Inc. incubated for later spun out from Affymax-GlaxoWellcome.[23]
From 1997 to 2009, Howard worked as Maxygen's CEO, focusing on human, including, protein pharmaceutical drugs and vaccine discovery, as core business. Non-core businesses were successively incubated, nurtured and spun-out (Codexis[26]) or sold (Verdia[25]). In 2008, he left Maxygen with $200MM in cash, no debt, on-going clinical stage drug development programs and multiple partnerships and licenses with other parties.
Following his departure, Howard started Oakbio, Inc., doing business as NovoNutrients Inc, a privately held Clean Technology company in Sunnyvale, California, USA. NovoNutrients captures CO2 from industrial waste gas streams and uses microbial chemosynthetic systems to capture and convert this carbon resource to protein-rich microbial biomass and valuable chemicals, sequestering a Green House Gas from accumulation in the atmosphere.
In 2012 Howard moved residency from Silicon Valley, California, where he had worked for 25 years, to Sydney, Australia.
From Sydney, Howard acts as Executive Chairman of NeuClone, Non-Executive Chairman of Immutep and Chairman of NovoNutrients.
Financing leadership
With Howard as CEO, Maxygen, Inc. completed its initial public offering of $110MM in 1999, just two years after its spinout from Affymax-GlaxoWellcome.[24] In March 2000, Maxygen raised another $150MM in a Secondary Public Offering. More recently, Howard and colleagues at NeuClone, Pty. Ltd. raised >$10 MM (AUS) from private investors in Sydney to support development of a portfolio of 10 biosimilar monoclonal antibodies.
Recognition & research
Howard has been awarded three Doctor of Science (honoris causa) degrees, one from the University of Technology, Sydney, Australia in 2004, one from the University of Queensland, Brisbane, Australia in 2008 and the third from the University of Melbourne, Melbourne, Australia in 2014. He was awarded the inaugural Grimwade Medal for Biochemistry, Department of Biochemistry & Molecular Biology, University of Melbourne, in 2016. Howard's >145 publications tackle topics ranging from the metabolism of the algae Caulerpa simpliciuscula, to the molecular pathogenesis of human cerebral malaria and the role of parasite antigenic variation and infected cell adherence in disease virulence. His papers reflect successful use of the tools of biochemistry, protein chemistry and structure-function, molecular biology, cell biology, large animal studies, and field studies with humans.
Patents
Howard is an inventor on nine patents. At the NIH he patented discovery, characterisation and cloning of a novel gene encoding a soluble malarial antigen, called PfHRP2[32] that the most lethal human malaria releases into the blood. This discovery led to a rapid, sensitive, inexpensive and reliable diagnostic test for malaria infection that the NIH licensed commercially.[33] This test has been used worldwide for over 15 years.[34] In 1990 and 1995, he and his colleagues at Affymax applied for the patents of antigenic determinants obtained using a pathogenic agent or a derivative that presents a restricted set of antigens, and recombinant DNA clone from Plasmodium falciparum. While working at Maxygen Inc., he and his colleagues developed three patents for the following technologies: antigen library immunisation using polynucleotides encoding flavivirus and alphavirus; multivalent antigenic polypeptides; and optimisation of immunomodulatory properties of genetic vaccines
↑ Pasloske, Brittan L.; Howard, Russell J. (February 1994). "Malaria, the red cell, and the endothelium". Annual Review of Medicine. 45 (1): 283–295. doi:10.1146/annurev.med.45.1.283. PMID8198384.
Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.
Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.
Duffy antigen/chemokine receptor (DARC), also known as Fy glycoprotein (FY) or CD234, is a protein that in humans is encoded by the ACKR1 gene.
CD36, also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
Plasmodium malariae is a parasitic protozoan that causes malaria in humans. It is one of several species of Plasmodium parasites that infect other organisms as pathogens, also including Plasmodium falciparum and Plasmodium vivax, responsible for most malarial infection. Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by P. falciparum or P. vivax. The signs include fevers that recur at approximately three-day intervals – a quartan fever or quartan malaria – longer than the two-day (tertian) intervals of the other malarial parasite.
Merozoitesurface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan. Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria. These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.
Southeast Asian ovalocytosis is a blood disorder that is similar to, but distinct from hereditary elliptocytosis. It is common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria.
Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.
Malaria culture is a method for growing malaria parasites outside the body, i.e., in an ex vivo environment. Although attempts for propagation of the parasites outside of humans or animal models reach as far back as 1912, the success of the initial attempts was limited to one or just a few cycles. The first successful continuous culture was established in 1976. Initial hopes that the ex vivo culture would lead quickly to the discovery of a vaccine were premature. However, the development of new drugs was greatly facilitated.
Malaria antigen detection tests are a group of commercially available rapid diagnostic tests of the rapid antigen test type that allow quick diagnosis of malaria by people who are not otherwise skilled in traditional laboratory techniques for diagnosing malaria or in situations where such equipment is not available. There are currently over 20 such tests commercially available. The first malaria antigen suitable as target for such a test was a soluble glycolytic enzyme Glutamate dehydrogenase. None of the rapid tests are currently as sensitive as a thick blood film, nor as cheap. A major drawback in the use of all current dipstick methods is that the result is essentially qualitative. In many endemic areas of tropical Africa, however, the quantitative assessment of parasitaemia is important, as a large percentage of the population will test positive in any qualitative assay.
Malaria vaccines are vaccines that prevent malaria, a mosquito-borne infectious disease which annually affects an estimated 247 million people worldwide and causes 619,000 deaths. The first approved vaccine for malaria is RTS,S, known by the brand name Mosquirix. As of April 2023, the vaccine has been given to 1.5million children living in areas with moderate-to-high malaria transmission. It requires at least three doses in infants by age 2, and a fourth dose extends the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.
Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models.
In molecular biology, apical membrane antigen 1 is a novel antigen of Plasmodium falciparum which has been cloned. It contains a hydrophobic domain typical of an integral membrane protein. The antigen is designated apical membrane antigen 1 (AMA-1) by virtue of appearing to be located in the apical complex. AMA-1 appears to be transported to the merozoite surface close to the time of schizont rupture.
Circumsporozoite protein (CSP) is a secreted protein of the sporozoite stage of the malaria parasite and is the antigenic target of RTS,S and other malaria vaccines. The amino-acid sequence of CSP consists of an immunodominant central repeat region flanked by conserved motifs at the N- and C- termini that are implicated in protein processing as the parasite travels from the mosquito to the mammalian vector. The amino acid sequence of CSP was determined in 1984.
KAHRP is a protein expressed by Plasmodium falciparum infecting erythrocytes. KAHRP is a major component of knobs, feature found on Plasmodium falciparum infected erythrocytes.
PfSPZ Vaccine is a metabolically active non-replicating whole sporozoite (SPZ) malaria vaccine being developed by Sanaria against Plasmodium falciparum (Pf) malaria. Clinical trials have been safe, extremely well tolerated and highly efficacious. The first generation PfSPZ product is attenuated by gamma irradiation; the second generation vaccines PfSPZ-CVac and PfSPZ LARC2 are, respectively, attenuated chemically and genetically. Multiple studies are ongoing with trials of the PfSPZ vaccines. All three products are produced using the same manufacturing process. These products are stored and distributed below -150 °C using liquid nitrogen (LN2) vapor phase (LNVP) freezers and cryoshippers.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells that are infected by the malarial parasite Plasmodium falciparum. PfEMP1 is synthesized during the parasite's blood stage inside the RBC, during which the clinical symptoms of falciparum malaria are manifested. Acting as both an antigen and adhesion protein, it is thought to play a key role in the high level of virulence associated with P. falciparum. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had antibody-binding (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called var. Each P. falciparum is able to switch on and off specific var genes to produce a functionally different protein, thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to endothelial cells, which facilitates further binding with uninfected RBCs, ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of P. falciparum malaria.
The Plasmodium helical interspersed subtelomeric proteins (PHIST) or ring-infected erythrocyte surface antigens (RESA) are a family of protein domains found in the malaria-causing Plasmodium species. It was initially identified as a short four-helical conserved region in the single-domain export proteins, but the identification of this part associated with a DnaJ domain in P. falciparum RESA has led to its reclassification as the RESA N-terminal domain. This domain has been classified into three subfamilies, PHISTa, PHISTb, and PHISTc.
Reticulocyte binding protein homologs (RHs) are a superfamily of proteins found in Plasmodium responsible for cell invasion. Together with the family of erythrocyte binding-like proteins (EBLs) they make up the two families of invasion proteins universal to Plasmodium. The two families function cooperatively.
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