INVESTMENTS IN BIOTECHNOLOGY 1993

BIOVST.ZIP release 1.7

October 30, 1993

INVESTMENTS IN BIOTECHNOLOGY

TABLE OF CONTENTS:

INTRODUCTION............................................2

GOALS OF MODERN BIOTECHNOLOGY...........................2

STRUCTURE OF THE BIOTECHNOLOGY INDUSTRY.................3

CURRENT INTERESTS OF THE BIOTECHNOLOGY INDUSTRY.........9

Drug discovery...................................10

Biomedicine:Diagnosis............................12

Biomedicine:Antibodies...........................13

Biomedicine:Immunology...........................15

Biomedicine:Interleukins and other cytokines.....20

Biomedicine:Nervous system.......................23

Biomedicine:Cancer therapy.......................26

Antisense........................................31

Transcription....................................32

Splicing.........................................34

Cell cycle.......................................34

Biomedicine:Virology.............................35

Biomedicine:Cardiovascular drugs.................39

Biomedicine:Wound healing........................39

Drug production..................................40

Drug delivery....................................41

Improvement of agricultural products.............42

Biological control...............................45

Marine biotechnology.............................45

Improvement of the environment...................46

ECONOMICS OF THE BIOTECHNOLOGY INDUSTRY.................48

INFORMATION ABOUT BIOTECHNOLOGY.........................51

INVESTING IN BIOTECHNOLOGY..............................53

SELECTED READING........................................54

APPENDIX A..............................................58

APPENDIX B..............................................59

APPENDIX C..............................................60

SHAREWARE...............................................62

REGISTRATION............................................63

INDEX...................................................64

UPGRADE CHANGES.........................................81

INTRODUCTION............................................#

INTRODUCTION

The biotechnology industry has suffered serious setbacks in

1993. A drop in stock prices for the biotechnology industry has

resulted from several blows to the industry: test results and the

political climate. A successful biotechnology industry is neces

sary, however, for the treatment of human disease, competitive

agriculture, and efficient management of the environment. The

biotechnology industry has developed with controversy since it's

inception in the 1970s. Recombinant DNA technology, patenting

life, and patenting DNA sequences have all been monumental deci

sions for society and its laws which were induced by the emer

gence of the biotechnology industry. The recent setbacks in the

industry provokes a reassessment of the industry in the United

States of America in order to maintain a fertile biotechnology

industry and the potential for profitability of investment in

biotechnology.

GOALS OF MODERN BIOTECHNOLOGY...........................#

GOALS OF MODERN BIOTECHNOLOGY

Manipulation of biology is desired to produce new drugs for

the treatment of human and animal disease, better agricultural

products, and a better living environment. Examples of new

desired products include: new drugs to treat and prevent infec

tious diseases, new drugs to treat cancer and aging, new and

improved agricultural products, new pesticides, and new products

to control environmental insults.

STRUCTURE OF THE BIOTECHNOLOGY INDUSTRY.................#

STRUCTURE OF THE BIOTECHNOLOGY INDUSTRY

Genentech, the founder company of modern biotechnology, has

grown to one of the largest of these firms with the development

of recombinant human insulin. Robert Swanson and Herbert Boyer

began Genentech in the early 1970s and it now has the "largest

center devoted to biotechnology", an $85 million facility."

Genentech was begun on the premise that "there was money to be

made in recombinant DNA". Genentech invests 50% of its revenues

on research and development compared to the average for the

pharmaceutical industry of 16.7%. The price of Genentech stock

has fared well during the recent slump in the prices of biotech

nology stocks, actually increasing. It has developed: recombin

ant human growth hormone (BioTropin), human recombinant insulin,

transforming growth factor-á-1 (TGF-á1), Activase to prevent

blood clotting which has decreased death rates by 25.9% in heart

attack patients, monoclonal antibodies to the HER-2 oncogene of

breast cancers, ç-Interferon (Actimmune has FDA approval for the

treatment of chronic granulomatous disease), Pulomzyme (DNAse

for the treatment of cystic fibrosis), a version of soluble CD4

for acquired immunodeficiency syndrome (AIDS) treatment, insulin

growth factor-1 (IGF-1), recombinant tumor necrosis factor and

others. A significant new product that they have recently

unveiled is a genetically modified human recombinant insulin that

can be processed by any cell in the body. This will lead to

novel gene therapy approaches to the treatment of diabetes and

other disorders.

Several organizations protect the interests of the biotech

nology industry. The Biotechnology Industry Organization (BIO)

has recently been formed by the merger between the Industrial

Biotechnology Association (IBA) and the Association of Biotech

nology Companies (ABC). BIO has taken the 500 employees from the

Industrial Biotechnology Association and formed this organization

of biotech companies, educational institutions, and state bio

technology centers. Dr. G.K. Raab, president and CEO of Genen

tech, is now the head of this organization as the elected chair

man of the board. The president, Carl B. Feldbaum, will involved

in battles with BIO against environment protection groups over

issues of food labeling and the use of new plant varieties. This

organization will serve to protect the interests of the biotech

nology companies. These interests will include concerns about

the patenting process and patent infringements. The ABC repre

sented the interests of smaller biotechnology companies and these

two organizations have differed on policy. They differed on

legislation for orphan drugs, for example. The Pharmaceutical

Manufacturers Association (PMA), which has some members in common

with BIO, is another interest group of biotechnology.

The biotechnology industry has recently been given competing

stock indices on the AMEX and the CBOE. On October 9, 1992 the

Chicago Board Options Exchange (CBOE) and the American Stock

Exchange (AMEX) simultaneously launched competing index options

to track the volatile biotechnology industry. The Amex's (BTX,

biotechnology stock index) is made up of 15 stocks and the CBOE's

(BGX) is made up of 20 stocks. The overlapping stocks of these

indices and the complete list of the AMEX's index are listed in

appendix A. The AMEX's (BTK) is "equal dollar weighted" to avoid

dominance of any one stock. At inception, it had a market capi

talization of about 16.8 billion. The CBOE's is "price

weighted", like the Dow, and at inception had a market value of

about 19.2 billion.

Because of the discovery nature of the biotechnology indus

try, it has induced monumental changes in patent laws and the

patent process. Since its inception in the 1970s, these changes

have occurred in: the patentability of a discovery, the patenting

process, the patentability of life, and orphan drug act legisla

tion. The Intellectual Law Association and the organizations of

the biotechnology industry (which includes BIO) protect the

interests of the patents. The patentability of genetically

engineered organisms was upheld in Diamond v. Chakrabarty in 1980

and transgenic plants and animals have since been deemed "patent

able". Harvard University received the first patent for a

genetically altered mouse, the "oncomouse", in 1988. The li

cense was sold to Dupont. This has allowed the rapid develop

ment of recombinant DNA in biotechnology. The patent process is

still in upheaval, however, several issues are still not settled,

first to invent versus the "first to file" and the usefulness of

an invention. In the United States of America, most university

scientists publish first and file for a patent application later.

This is not true in most countries. In Europe and most foreign

systems, once a discovery is published, the inventor loses the

right to a patent. An invention must be "useful, novel, and non-

obvious" in order to be patentable. Novelty in United States

patent law is: "An invention not known or used by others in USA

or described in a printed publication...before the invention date

and not described in a printed publication or in public use or on

sale in the United States of America more than one year before

the United States application date". In such a case, the patent

obtains a 17 year monopoly for the invention. The United States

of America has been negotiating a universal patent agreement with

the with the World Intellectual Property Organization with a

move toward the "first to file" rather than "first to invent"

principle. In a recent case, however, the "first to invent"

rule was upheld. On February 17, 1993, the U.S. Patent and

Trademark Office determined that claims in a Regeneron patent

application involving human ciliary neurotrophic factor (CNTF)

protein and their pharmaceutical compositions containing it were

allowable since they were the first to make the invention. This

is despite the fact that Synergen was the first to receive a

patent for CNTF in May 1991. CNTF is now in clinical trials for

treatment of Lou Gehrig's disease. In the last couple of years,

there has been a dispute about the patentability of DNA sequenc

es. The National Institutes of Health (NIH) sought to patent DNA

sequences that were found with expression tags. This would allow

NIH to patent DNA sequences for proteins with unknown functions.

If NIH had won this patent, it was argued that it would stifle

future research on those genes. A similar case is under scrutiny

yet. Researchers at Stanford want to patent sequences of the T

cell receptor. This is because mutations in these genes may lead

to autoimmunity, rheumatoid arthritis and multiple sclerosis.

They seek to patent only specific uses, however, and the problem

of ownership is therefore avoided. The Orphan Drug Act is a

recent addition to laws brought about by the modern biotechnology

industry. The United States Orphan Drug Act was established in

1983 to promote the development of drugs for rare diseases.

Fifty drugs have since been approved for 59 conditions. There

are still a number of scientific and legal aspects of this act

which need to be refined. But this act will allow no other

patents on the same structure for the same condition for seven

years. If it is of a similar structure, it must be shown to be

better in clinical trials.

The drug evaluation process is under currently under scruti

ny in the United States of America as well. The method of drug

evaluation depends upon the organism for which the drug is being

developed. Drugs to be utilized for humans undergo pre-clinical

trials and phase I, II, and III trials. Pre-clinical trials

decide upon the efficacy and safety of the approach of the drug

and are based upon animal and in vitro studies. Clinical trials

occur sequentially with evaluation after each trial: Phase I

trials establish that a drug is safe for human use on healthy

volunteers, Phase II trials establish that the drug is effective

and what dose is effective with a small number of patients, and

phase III trials establish the dose and the effectiveness of the

drug on a large number of patients. The data from the clinical

trials are then submitted to the FDA for approval. A suggestion

has been suggested to improve the phase II studies and discontin

ue or reduce the size of phase III clinical trials. This would

decrease the time required for the commercial development of

products for therapeutic use, which is now an average of eight

years. Risk models for the evaluation of patients are important

for the outcome of clinical trials of many of the newer biotech

nology drugs. An example of the use new methods for the analysis

of clinical data is a risk model based upon the APACHE III(TM)

database. It is being used to monitor patients with systemic

inflammatory response syndrome (SIRS). Cortech, Inc. is using

this model in Bradycor clinical trials and describes the model

as: "..the state of the art analytical tool for evaluating the

benefits of sophisticated drugs in complex diseases". The APACHE

III model, allows data on patients to be to analyzed according

to their individual risk of mortality. It is accepted throughout

the world for scoring the severity of illness in critically ill

people. The APACHE method allows one to find patient subgroups

according to their risk profiles. Statistical methods such as

the APACHE III method increase the power of a test. This means

that they are more likely to find a difference between the treat

ment and the control groups. Therefore, the subgroup which can

benefit most from a drug can be determined. In other words, a

drug which is effective in the treatment of diseases may be found

ineffective by some statistical methods if the power of the test

is poor. The Apache III (TM) risk model was derived from the

analysis of over 100,000 patients within the APACHE III Interna

tional Database.

CURRENT INTERESTS OF THE BIOTECHNOLOGY INDUSTRY.........#

CURRENT INTERESTS OF THE BIOTECHNOLOGY INDUSTRY

Modern biotechnology has made significant contributions to

new methods of drug discovery, production, and delivery. New

drugs include the new antibodies, soluble receptors, recombinant

proteins, peptides, nucleic acids and derivatives of nucleic

acids. These are used for treatment and for diagnosis of dis

ease, the improvement of the environment, and better agriculture

methods.

HEADINGS:

Drug discovery

Diagnosis

Antibodies

Immunology: vaccines,allergies, and transplantation,

Interleukins and other cytokines

Nervous system disorders

Cancer therapy

Antisense

Transcription

Splicing

Cell Cycle

Virology

Cardiovascular drugs

Wound Healing

Drug production

Drug delivery

Agriculture

Biological Control

Marine Biotechnology

Environment

Drug discovery...................................#

Drug discovery

Biotechnology requires compound discovery. Old discovery

methods relied on screening of a large number of compounds for a

desired bioactivity. Compound libraries or organisms are

screened for the production of molecules based upon pre-deter

mined desired criterion. This has been used for discovering

antibiotics in the past, and still is uses by some companies for

drug discovery. Screening organisms for useful drugs is still

used by a number of drug firms. There are basically two ap

proaches to this: (1) screening libraries of compounds or pro

ducts of organisms for a desired activity and (2) The screening

of organisms known to be resistant to certain infections or

growth inhibit other organisms. One of the most recent com

pounds discovered by screening a large number of compounds for a

desired activity is taxol. Taxol has been approved for treatment

of ovarian cancer and is being produced by Hauser of Boulder,

Colorado for ovarian cancer. Drug screening technology itself

is a large part of modern biotechnology. Corporations, such as

Pfizer, Inc., utilize high throughput screens to find novel

compounds as well. A more modern variation to this approach is

being used by some companies by developing large peptide libra

ries which are screened for binding to a structure or for bioac

tivity. Affymax, Selectide, and Enzon all have examples of this

approach. Recombinant Fab combinatorial libraries have been

developed for this purpose as well. Fab fragment libraries

created from B cell RNA have been cloned into phagmid libraries

to be screened for pre-determined binding specificities (Strata

gene). Isolation of drugs based upon an organism's traits, such

as resistance to infection is also an active area of biotechnolo

gy. For example, the biological activity of squalamine was

recently found this way. The dogfish, which is resistant to in

utero microorganism infections produces squalamine. This com

pound has been very active against Streptococcus sp., Staphylo

coccus sp., Escherchia coli, and yeast. Other companies are

offering drug screening technologies for custom profiles of

biomolecules after they are discovered to determine the spectrum

of activities for it. This is offered by Oncogene Sciences as

the GEMS(TM) discovery system.

Techniques for the discovery of drugs have recently been

under scrutiny for patentability. The patenting of the polymer

ase chain reaction (PCR) by Cetus has been one of the newest

discovery methods with great impact to biotechnology. Cetus has

since sold the patent to Hoffman-LaRoche. PCR, is a reaction

where complementary DNA oligonucleotides are used to clone se

quences from DNA or RNA. A heat stable polymerase, taq polymer

ase, is used to amplify the sequence in between the areas where

the primers have annealed. In this way, if one knows flanking

sequences of genes, genes can be cloned right out of an organisms

DNA or RNA with very little analysis and time required. This all

takes place in a computer controlled apparatus made by Perkin

Elmer. Cetus has allowed the use of PCR in research, but the

availability of other polymerases (cheaper), has instigated a

crackdown on this patent by Hoffman-LaRoche. Hoffman-LaRoche,

the Swiss based pharmaceutical company, has initiated a suit

against Promega, Corp. of Madison, WI. Promega was licensed to

make and sell taq polymerase for a limited number of applications

which did not include PCR. They were undercutting Perkin-Elmer's

prices by up to %60. Other techniques which are likely come

under such scrutiny in the future include methods for sequencing

the human genome.

Biomedicine:Diagnosis............................#

Biomedicine:diagnosis

Genetic techniques for disease diagnosis play an extensive

role in modern biotechnology. New technologies include: FISHing

(Fluorescent in Situ Hybridization), PCR, and enzyme labeled gene

tag reagents. With the new technologies available, specific

translocations of genes involved in malignant transformation can

be found with greater precision. Furthermore, specific disease-

causing genes can be searched for and found in individuals for

genetic counseling purposes. PCR techniques can now be used to

specifically determine the presence of viruses in tissues provid

ing a direct link to viral infection, rather than just an asso

ciation of the change in antibody titer of patients or victims.

This has been used recently for the Four Corners Flu that has

occurred in the northern New Mexico-Arizona area. The Hantavirus

has been found in victims. This virus is transmitted to them by

rodents that live in the area. Genetic data for the presence of

the virus was found by PCR in tissues from the victims and deer

mice. Biotechnology companies are also developing genetic tech

niques for the diagnosis of the involvement of specific oncogenes

in cancer. For example, Oncogene Sciences has developed a hy

bridization probe kit for chronic myelogenous leukemia and there

are kits available for other translocations as well.

Biomedicine:Antibodies...........................#

Biomedicine:antibodies

Antibodies are used for a number of purposes in biotechnolo

gy. Two basic types of antibody preparations are utilized, poly

clonal and monoclonal. Polyclonal antibodies, heterologous

antisera, immune globulin, or hyperimmune globulin are produced

by whole living organisms. Monoclonal antibodies are produced by

the fusion of a myeloma cell with immune lymphocytes. The pro

duct is a cell line that produces only one antibody that binds a

desired determinant. Antibodies are useful for a number of

things in biotechnology. First, they are very useful for prophy

laxis against known exposure to pathogens or toxins. MedImmune

is developing a number of antibodies for this purpose including

polyclonal antibodies for prophylaxis against respiratory synci

tia virus (RSV) and cytomegalovirus (Cytogam) and a monoclonal

antibody for AIDS (Medi488). North American Biologicals, Inc.

has been given rights to HIVIG by Abbott, a polyclonal antibody

preparation from health HIV-infected individuals. This will be

used to attempt to prevent the spread of HIV to the infants of

pregnant women in a trial to begin soon. One in five women

transmit the virus to their infant in Utero or at birth. Gen

zyme, Inc. has entered into an aggreement with Univax Biologi

cals, Inc. to produce drugs for the treatment of diseases asso

ciated with cystic fibrosis. Neozyme II will be given the li

cense and development rights for these drugs from Genzyme, Inc..

HyperGam + CF will be used to give passive immunity to Pseudomo

nas infections. Pseudomonas spp. are responsible for life-threa

tening infections in cystic fibrosis patients. Second, they

play a very significant role in diagnostic reagents. This in

cludes bacterial and viral pathogens as well as cancers. For

example, kits have been developed recently with monoclonal anti

bodies that can detect ras oncoproteins. These proteins are

often involved in the development of aggressive cancers and may

be involved in as many as one fifth of all cancers. Third,

monoclonal antibodies have been developed for the treatment of a

number of disease conditions and are in various stages of devel

opment. These include antibodies to tumor necrosis factor (a

cytokine involved in septic shock) and antibodies to target

tumors with cytotoxic drugs or radiation for cancer therapy.

Seragen is developing fusion toxins which target activated T

cells via the IL 2 receptor. So far, this treatment will be used

for rhematoid arthritis, certain cancers (chemotherap resistant

lymphomas) type I diabetes, and HIV infection. Furthermore,

idiotype vaccines (killed MBP-reactive T cells are used to immun

ize against MS) have shown some promise and are in phase I trials

Most antibodies in use are products of animals other than humans,

therefore, because of species differences in their amino acid

sequences, they can be recognized by the immune system of another

animal. This is why humanized antibodies are being developed by

a number of companies, to avoid rejection of the antibody in

humans by the immune system. Humanized antibodies are the result

of the genetic engineering of antibodies of other species with a

desired reactivity for human treatment or prophylaxis. They have

been modified to be as similar to natural human antibodies, while

maintaining the desired reactivity. Companies in clinical trials

with humanized antibodies include: Cytogen, Genentech, IDEC

Pharmaceuticals, Protein Design Labs, and Scotgen Biopharmaceuti

cals. New methods of achieving humanized antibodies include the

use of mice which are transgenic for a mini-human antibody locus.

This is being are being tried by GenPharm of Mountain View, CA.

In this way,

these mice can be injected with a desired immunogen, and the

monoclonal antibodies produced can be screened for only the

antibodies of human sequence. They will not have to be modified

by further genetic engineering because they already contain only

human sequences. Lastly, antibodies and derivatives of them are

being used in medical imaging. For example, they will allow

better localization of areas for surgical removal of cancer

tissue.

Biomedicine:Immunology...........................#

Biomedicine:immunology

Vaccines are a large part of the biotechnology industry and

remain the only method of combating many diseases, particularly

viruses. The most celebrated vaccines are now the vaccines

against the human immunodeficiency virus (HIV) virus. Both,

vaccines aimed at preventing infection with the HIV virus and

AIDS and novel vaccines aimed at quelling the disease after

infection are being developed. Immune Response Corporation

released the results of its first clinical trial of a novel

vaccine designed to quell AIDS disease on June 13, 1993. A whole

virus preparation was used in which the virus has been chemically

stripped of its envelope. A study of 103 patients suggested

that those who received the experimental vaccine maintained

slightly reduced levels of virus. Although the results are

promising, it is less of a response than is desired for an AIDS

treatment. Some virologists have said that the differences were

so slight that the results were impossible to interpret.

Several biotechnology companies have taken the same approach to

stimulate the cellular immune response with particular proteins

of HIV. Furthermore, this vaccine may be used for the prevention

of infections. It has been shown that a small proportion of

people who have been infected with the HIV virus do not develop

AIDS and their antisera never tests positive for HIV. Cellular

immune responses can be detected, however. Alpha-1 Biomedical of

Washington D.C. and Cell-Sci of Alexandria, VA are developing

these vaccines. They are utilizing HGP30, the P17 core protein

of HIV, which is expressed very early in HIV infection. The

vaccine is actually being produced by Viral Technologies, Inc..

So far, clinical trials have detected no side effects for this

vaccine. The most popular approach, and probably the most

likely to succeed for protecting individuals from infection, will

probably involve the stimulation of neutralizing antibodies or a

combination of stimulating both cellular and humoral immune

responses. If the HGP30 vaccine approach is utilized it is hoped

that a combined vaccine will be used which stimulates both the

cellular immune response and antibodies. Neutralizing antibodies

are directed against gp120 (or gp160, an unprocessed viral pep

tide containing gp120). This is the protein that binds the CD4

molecule on T cells which the HIV virus uses to enter the cell.

A number of companies are developing these vaccines. Mammalian

versions of the gp120 vaccine are being developed for the LAI

(French isolate first discovered) and MN strains of HIV by Genen

tech. This will have the post-translational carbohydrate addi

tions of mammalian cells. A mammalian version of the SF-2 strain

is being developed by Biocine/Chiron. MicroGeneSys is developing

the gp120 and gp160-protein-based vaccines from the LAI strain in

insect cells with baculovirus vectors. These cells produce a

protein with some of the carbohydrates attached that mammalian

cells add. The gp160 molecule is being used in an approach

similar the above cellular immunity vaccine, HGP30. It is being

used on HIV-infected pregnant women to prevent transmittance to

the fetus. It is hoped that it will stimulate both cellular and

humoral immunity and prevent the transplacental transfer of HIV

to the fetus. This vaccine (VaxSyn) has also been approved by

federal government for HIV-infected armed service personnel.

Immuno AG has the version of this vaccine which is expressed in

mammalian cells. Vaccines which stimulate the antibody response

to prevent HIV infection can utilize the gp120 molecule or

synthetic peptides of the gp120 molecule. Peptides which corre

spond to the V3 region of the gp120, a region which mutates

frequently, are being developed by Repligen. A cocktail of a

number of peptides corresponding to the sequence of the V3 re

gions of a number of HIV isolates is being developed which is

hoped to induce immunity to the large number of mutants of HIV.

Since these peptides are often not very immunogenic, powerful

adjuvants will need to be used. One such adjuvant, Stimulon with

QS-21, has been developed by Cambridge Bioscience. Genentech has

chosen this adjuvant for use with its gp120 vaccine as well. A

number of other modern vaccines are also being developed by the

biotechnology community. One such approach utilizes the B sub

unit of cholera toxin which is a mucosal adjuvant. Mucosal

immunity has been achieved for SIV (simian immunodeficiency

virus) in monkeys. More "high-tech" approaches to vaccines are

also being developed against the AIDS virus and other organisms.

They involve the use of live vectors for delivering the immuno

gen. Recombinant proteins, such as gp160 or gp120 are being

placed in Vaccinia vectors (modified Small pox viruses) or BCG

(Bacillus Calmette-Guerin). These vectors stimulate both cellu

lar and humoral immunity. Bristol-Myers Squibb has a version of

this vaccine. It is a gp160-vaccinia recombinant vaccine. Other

modern vaccines are being developed to a number of pathogens.

MedImmune itself is developing a number of modern vaccines

against AIDS, parvovirus, and Lyme disease. Abt Associates of

Cambridge, MA and Family Health International of Research Trian

gle Park have been awarded this a 6.5 million dollar contract to

test the AIDS vaccines.

Treatment of allergic reactions to a number allergens has

been undertaken by modern biotechnology companies. ImmunoLogic

Pharmaceutical Corp. is developing Fel D I as CATVAX and AllerVAX

for the treatment of two common allergies, allergies to cats and

ragweed. CATVAX is now in phase II clinical trials.

Transplantation is an important area of research in biotech

nology today. Two of the most popular drugs in transplantation

immunology, used for inhibiting the rejection of transplants, are

cyclosporin A and FK506. These drugs can be taken orally and act

by inhibiting the activation of T cells. This is accomplished

mainly by the inhibition of a T cell transcription factor, NF-AT.

Serious side effects still occur with these drugs, which include

renal toxicity and neurotoxicity. Adhesion molecules are now in

vogue today and a large number of biotechnology companies are

devoted to studying these molecules. Newly discovered adhesion

molecules have been targeted to inhibit transplant rejection.

Adhesion molecules can be classified by their necessity for

signaling by T cells the immune system, these cells are respon

sible for graft rejection and the initiation of many immune

responses. The LFA 1, CD5, and CD2 molecules are not involved

in cell signaling, but increase the avidity of the interaction of

the lymphocytes with antigen presenting cells or targets. CD4 or

CD8 molecules are involved in signaling as are the antigen spe

cific receptors of T cells. A recent addition to adhesion recep

tors of T cells involved in signal transduction is the CD28

molecule. This molecule binds the B7 ligand and this interac

tion is necessary for the generation of cytotoxic T cells.

Cytotoxic T cells are involved in the removal of virus-infected

cells as well as the rejection of tumors and grafts. Molecules

similar to CD28 which block the interaction of CD28 with B7 have

been used for blocking allograft rejection. CTLA4Ig is one such

drug that has inhibited graft rejection.

The treatment of autoimmune diseases is being targeted by

modern biotechnology as well. New MS treatments are described in

the section on nervous system drugs. Similar treatments are

being considered for other autoimmune diseases such as rheumatoid

arthritis. Seragen is developing new treatments for autoimmune

diseases and HIV by targeting activated T cells via their IL 2

receptor with fusion toxins.

Biomedicine:Interleukins and other cytokines.....#

Interleukins are cytokines which allow intracellular commu

nication between cells of the immune system. There are now 14

interleukins numbered 1-14. Other cytokines of current interest

in biotechnology include: TGF-à, EGF, FGF, TGF-á, TNF-à,TNF-á,

CNTF, BDNF, neuroleukin, NGF, IGF, interferons, and Stem cell

factor (SCF).

The Interleukin 1s: Interleukin 1s are a family of structurally

related cytokines that all bind to two different receptors. This

family of proteins is composed of IL 1à, IL 1á, and IL 1ra.

These molecules are involved the initiation of immune response

(proinflammatory) and in the acute phase response of the liver.

Furthermore, receptors can be found in the neuroendocrine and

cardiovascular system. It is one of the cytokines responsible

for septic shock and is involved in the stress response and the

secretion of glucocorticoids.

Interleukin 2: Interleukin 2 is the first T cell growth factor

which was characterized, isolated, and cloned by recombinant DNA

methods. For this reason, this cytokine has been under investi

gation for the treatment of immune disorders and to generated

immune cells capable of killing cancer cells. This has worked to

some extent with cells called "lymphokine activated killer" or

LAK cells. Immune cells are treated in the laboratory with IL 2

and then readministered to cancer patients. Systemic use of IL 2

has proven to have too many side effects. Another approach to

kill tumor cells has involved transfecting tumor infiltrating

lymphocytes (TILS) with the IL 2 gene in the hope of delivering

the IL 2 to tumors locally. These studies are being performed by

the National Institutes of Health.

Interleukin 3: Interleukin 3, also known as multi-CSF (colony

stimulating factor) promotes the differentiation of early T cell

precursors, supports the establishment of T cells lines and

supports the proliferation of a broad distribution of hematopoie

tic stem cells. Furthermore, it synergizes with a number of

cytokines in colony formation by primitive stem cells (CD34+

cells).

Interleukin 4: Interleukin 4 was first characterized as a B cell

cytokine; however, it has turned out to be an important T cell

growth factor as well. It is involved in the growth of cytotox

ic T cells and T cells that collaborate with B cells and it is

absolutely required for IgE production. Anti-IL 4 antibodies

have proven to be useful in some types of vaccination, skewing

the development of T cell subpopulations: favoring T inflammatory

(IL 2 producing) cells in mice. Furthermore, renal cancer has

been treated in mice by the transfection of the tumor cells with

the a functional IL 4 gene. Genetic Therapy, Inc. has produced a

retrovirus which produces IL 4 for the treatment of melanomas,

kidney cancer, breast cancer, and colon cancer.

Interleukin 5: Interleukin 5 is involved in B cell proliferation

and differentiation. Furthermore, it acts as an eosinophil

growth factor and is thus involved in parasite and tumor immuni

ty.

Interleukin 10: Inteleukin 10 is produced by TH2 cells, which are

responsible for the production of IL 4. It will inhibit the

production of TH1 cells (IL 2 producing).

Interleukin 12: Inteleukin 12 is produced by macrophages in

response to stimulus, such as Listeria. This cytokine is respon

sible for the development of TH1 cells. The loss of TH1 cells is

now believed to play a role in AIDS.

Interleukin 13: Interleukin 13 inhibits the secretion of inflam

matory cytokines in response to sepsis (See Interleukin 1).

Furthermore, it synergizes with Interleukin 2 in the induction of

interferon-ç production.

TNF: Cachectin and lymphotoxin are the tumor necrosis factors,

TNF-à and TNF-á. TNF-à is involved in septic shock and antibod

ies to it are being considered for treatment of septic shock.

Gene transfection experiments are also being performed with this

cytokine which are analogous to the IL 2 transfections. TILs are

being transfected in the laboratory and transferred back to the

patient.

TGF-ás: TGF-ás have pleotropic effects on many cell types

including immune cells and fibroblasts. They are involved in

immune memory, immune suppression and wound healing.

Transforming growth factor-ás (TGF-ás) (Genentech:TGF-á1, Cel

trix: TGF-á2, and Oncogene Sciences:TGF-á3), are members of a

family of over 18 proteins. These cytokines are being developed

to treat chemotherapy side effects, ischemic heart injury, and

wound healing disorders.

Cytokine combinations: The use of combinations of cytokines for

the purpose of treatment of disease or the growth of desired

cells is being performed by a number of companies. Cell-Sci is

one pioneering company which is doing this with "Multikine".

Amgen has also been involved in this research. One cytokine

combination which has proven useful for the purpose of growing

stem cells (CD34+, see stem cells) is the combination of Stem

cell factor (SCF) with other synergizing cytokines such as G-CSF,

GM-CSF, Erthyropoeitin (EPO) and IL 3.

Biomedicine:Nervous system.......................#

New drugs have been found for a number of nervous system

disorders including, brain tumors, amyotrophic lateral sclerosis

(Lou Gehrig's disease), and multiple sclerosis (MS). Betaseron,

a form of á-interferon (IFN-á1b), has recently been approved for

use by Chiron Corp. as the first licensed treatment for MS. It

is the only drug "specifically approved" for the treatment of MS.

The drug is being produced by Berlex, a unit of Schering AG

(SCHG.F). MS affects 250,000 to 300,000 Americans. MS is medi

ated by T cells which react with the myelin basic protein (MBP)

of the central nervous system. á-interferon is produced by

suppressor T cells and it is therefore hoped that the administra

tion of Betaseron to MS patients will suppress the MBP-reactive T

cells. This drug is not a cure and other more effective drugs

are needed. However, it has been claimed that this drug is as

effective as other drugs at controlling the disease. The admin

istration of 8 million units of Betaseron every other day de

creased the relapses and the number of patients with detectable

brain lesions compared to placebo controlled "relapsing-remitting

MS". In the one study performed so far, twenty nine percent of

the placebo patients had brain lesion detectable by Magnetic

resonance imaging (MRI) while only 6% of the Betaseron treated

had the lesions. Furthermore, the number of attacks was de

creased, 0.9 vs 1.31 per year. Other drugs, specifically target

ing the MBP-reactive T cells are being developed and will prob

ably be more effective. Drugs such as toxin-conjugated antibod

ies which target the activated T cells and the T cells with the

receptors specific for MBP are being developed by a number of

companies. The induction of oral tolerance to MBP by feeding

patients the whole protein has also shown great promise (Selected

reading, Weiner et al.). Similarly this is being tried for

rheumantoid arthritis by feeding individuals collagen.

One obstacle to treatment of neurological disorders has

already been overcome. Getting drugs across the blood brain

barrier, BBB. The BBB does not allow large molecule to pass

across it. T cells get there only because they are activated and

are able to induce their transport across the barrier, transient

ly. Several companies, Alkermes and Cambridge Neuroscience, have

been able to target receptors at the BBB with antibodies and have

gotten drugs to pass into the brain. Therefore, drugs such as

antibodies, cytokines or peptides may be targeted across the BBB

where they can be effective. One cytokine which may be used for

the treatment of neurological defects or for the prevention of

neurological defects due to ischemic injury is nerve growth fac

tor, NGF. NGF has been shown to protect neurons from apoptosis

(a form of programmed cell death). Nerve growth factor is also

being explored for its ability to inhibit neuron death in the

case of brain trauma. Cephalon produces NGF as a nerve protector

and has been targeting the BBB as well.

Molecular surgery for the treatment of brain tumors may be

possible soon as well. Retroviruses with the Herpes Simplex

Virus thymidine kinase gene (HSV-tk) were introduced into rat

brain tumors by HSV-tk-transfected fibroblasts. The rats were

then treated with a drug that will kill a cell containing the

HSV-tk gene, gancyclovir. Complete tumor regression was ob

served.

New drugs are being produced by biotechnology for the treat

ment of peripheral nerve abnormalities as well. Ciliary neuro

trophic factor (CNTF) is now in clinical trials for amyotrophic

lateral sclerosis (ALS or Lou Gehrig's disease). Regeneron is

now finishing phase II clinical trials. This protein drug has

been shown to inhibit apoptosis (programmed cell death) in neu

rons. Interestingly, the gene responsible for familial ALS has

been shown to be the Cu/Zn superoxide dismutase gene. The pro

duct of this gene protects cells from radicals. Free radicals

are chemical agents that induce damage in the cells molecules,

such as their DNA. Furthermore, a protein which is believed to

monitor DNA integrity, p53, is involved in the induction of

apoptosis. It may be that CNTF will inhibit the apoptosis in

duced by this gene by this mechanism. Phase II clinical trials

for CNTF have been disappointing, in most cases showing no dif

ferences between treatment and control groups. Although it has

been shown to be safe, antibodies to CNTF developed in all pa

tients. Furthermore, some patients developed elevated tempera

ture, diarrhea, cold sores, and anorexia. One group of patients

patients in the Regeneron study may have shown a response to

CNTF. Those given high doses (12 patients) demonstrated less

deterioration of muscle strength (72%) and lung function (44-69%)

than the group that received the placebo (14 patients). It

should be pointed out that the original study was composed of 240

patients: one third was to receive 30æg/kg of CNTF, one third was

to receive 15æg/kg, and one third was to recive a placebo. The

phase III clinical trials are designed for a 95% probability of

determinng if CNTF is effective. Synergen an Syntex are planning

phase II/III studies of CNTF. So far, the side effects are the

same as those observerd in the Regeneron study. BDNF (brain

derived neurotrophic factor) is also currently being considered

by Amgen and Regeneron for treating ALS. It has been shown to

protect neurons as well. Other drugs which will decrease radi

cals in cells are also being explored. Vitamins C and E will do

this as well.

Biomedicine:Cancer therapy.......................#

Biomedicine:cancer therapy

Many new approaches to the treatment of cancer are under

investigation by modern biotechnology. Drugs which kill dividing

cells are the most frequently used today. These non-specific

drugs have the problem of killing many normal cells as well as

tumor cells. Most notably, they kill lymphocytes. Furthermore,

tumor cells often become resistant o these drugs by the up-

regulation of a multiple drug resistance gene. This leads to the

overproduction of P-glycoprotein and the resistance to a large

number of chemotherapeutic agents. Therefore, new approaches

should be more specific for the cell type, will hopefully have

less toxic side effects, and be less prone to multiple drug

resistance. The goal is to be more specific and more efficient

at killing tumor cells. This is being approached at several

levels: cell surface growth factor receptors, intracellular

second messengers for growth factor receptors, and the transcrip

tion of nuclear oncogenes, the introduction of normal tumor

suppressor genes and new methods of immunotherapy. Drugs which

are targeting the activation domains of tyrosine kinases are

being developed by a number of the above mentioned methods. It

is hoped that drugs which are very specific for the tyrosine

kinases responsible for altered signaling in cancer cells will be

found. For example, drugs which will target SH2 and SH3 domains

of a cell-type specific tyrosine kinase would be more useful than

drugs which inhibit any dividing cell. Drugs which inhibit Ras

oncogenes are being studied by a number of companies. Most

recently, Merck Research Laboratories in West Point, PA and

Genentech, Inc. of S. San Francisco, CA, have been looking for

drugs that inhibit the post-translational modification of the ras

oncogenes. In order to function efficiently, the ras oncogenes

require membrane association via a farnesyl group. Several

custom drugs have been found by these groups which will act in

low concentrations (micromolar). Furthermore, no toxicity has

been found yet in vitro. Ligand Pharmaceuticals of San Diego, CA

is another company developing small molecules with propriety

technology which target intracellular receptors (IR) for hormone

receptors. Targeting the ligands for growth factor receptors is

being preformed by a number of biotechnology companies as well.

Antagonists, soluble receptors, or neutralizing antibodies to

the ligands which cause the aberrant growth of cells are being

sought and developed. The aberrant production or control of

transcription factors has been shown to cause the transformation

of many cell types. Therefore, an approach with great promise is

to find a method of inhibition of these aberrantly controlled

transcription factors. Oncogene Sciences has made a commitment

to this and have developed diagnostic reagents for translocations

involved in leukemia and is focusing a large part of their com

pany's effort on transcription factors. Furthermore, the have

developed diagnostic reagents for mutations in the ras oncogene.

This oncogene is involved in a number of aggressive malignan

cies.

Tumor suppressor genes are now a very active area of cancer

research. These are genes which normally inhibit the growth of

cells; the loss of their function causes transformation. The

retinoblastoma protein (RBP), p105 and p53 examples of these

genes. Transfection of transformed cells with a wild type p53

has been shown to cause the reversion of these cells to a normal

phenotype. Onyx Pharmaceuticals is committed to the production

of "small molecule therapeutics for cell growth and differentia

tion". This California company was formed in 1992 from the

molecular oncology group of Cetus, Corp. and it is financed by

three venture capital firms and Chiron, Corp. The will be

specifically targeting the ras gene superfamily and tumor sup

pressor genes. Genetic therapy for lung cancer is being consid

ered as well. A retrovirus containing the antisense k-ras gene

or wild type p53 will be used to attempt the transfer of these

genes to the tumor cells to regulate their growth.

New cancer treatments based upon immunotherapy have shown

alot of promise recently. As mentioned above, some T cell

adhesion receptors are involved in signal transduction. This is

the CD28 molecule and the B7 ligand. This interaction is neces

sary for the efficient generation of cytotoxic T cells. Cytotox

ic T cells are involved in the removal of virus-infected cells as

well as the rejection of tumors and grafts. This molecule or

modifications of similar B7 binding molecules (CTLA4Ig) have been

used to prevent graft rejection and to generate cytotoxic T cells

which cause rejection of tumors in mice.

Transfection of effector T cells with genes that encode the

T cell receptors (TCR) which recognize tumor-specific antigens

have demonstrated success in a limited number of cases. Specifi

cally, a lymphoma caused by the Epstein-Barr virus (EBV). T

cells from a sibling were transfected with the TCR genes and then

administered to the patient. Other treatments are being devel

oped for other tumors with the same approach: the targeting of

viral tumor antigens. Targeting tumor specific antigens is also

being considered for the treatment tumors of non-viral origin.

Furthermore, processed peptides of oncogenes are being consid

ered. The mutation of proto-oncogenes causes the formation of an

oncogene and often a cancerous cell. This can be a "single hit"

of a "multiple hit", i.e the result of one oncogene or the result

of several oncogenes. Some oncogenes may be processed by the

cell and present the "oncogene-specific" peptide to autologous T

cells. For example, ras mutants have been considered. Vaccines

are being attempted which will generate these T cells.

Stem cells are progenitors of mature cells in the organism.

There are many different types of stem cells. These cells will

be useful for replacement cell therapy and gene therapy. Stem

cells of the immune system are the most noteworthy at this time.

These cells are capable of generating many mature cell types of

the immune system. Cellpro, Inc. of Bothwell, WA has been able

to isolate hematopoietic stem cells. Using a monoclonal anti

body that defines a determinant CD34 (cluster of differentiation

number 34) they have isolated hematopoietc stem cells by positive

selection with their patented CEPRATE system. The patients bone

marrow cells are labeled with the anti-CD34 monoclonal antibody

and are then passed over a column that will bind that antibody.

The cells are then positively selected by washing them off of the

column with an acid wash. This removes the cells from the column

and the antibody from the cells. Applied Immune Sciences has a

similar cell separation system, the AIS MicroCELLector. These

stem cells have also been grown with the use of stem cell factor

(SCF) in vitro. It has been found that the administration of

these stem cells to cancer patients after treatment with drugs

such as Cytoxan and Thiotepa with G-CSF (granulocyte-colony

stimulating factor, Amgen's Neupogen) has significantly decreased

their chemotherapy side effects. GM-CSF (granulocyte macrophage

colony stimulating factor, Immunex's Sargramostim) is also under

investigation for these treatments. A study is presently being

performed with this protocol followed by taxol treatment for

ovarian cancer. Similar treatments are in phase I and phase II

clinical trials for non-Hodgkin's lymphoma and breast cancer.

CD34+ cells have also been used for allogeneic bone marrow trans

plantation with good results. Cellpro, Inc. is expected to get

half of this market. Future prospects for CD34+ cells include

genetic engineering applications. If these cells are modified

with a gene to deliver a drug, they may be present in the body

for a longer period of time than more differentiated cells. TGF

á3 (see Cardiovascular drugs) is also being developed for cancer

therapy. It will be used to decrease side effects caused of

chemotherapeutic drugs, such as oral mucositis. Oral mucositis

is a painful wound healing disorder.

Antisense........................................#

Antisense

Antisense drugs are some of the most promising drugs which

are on the verge of an explosion in use. Prototypes of these

drugs have been used to: inhibit gene function for the treatment

atherosclerosis in animals, inhibit tumor causing retroviruses in

mice, inhibit oncogene transcription, inhibit of virus produc

tion, inhibit pigment production in flowers, and inhibit the

breakdown of tomatoes. Antisense compounds aimed at papilloma

virus infections, cytomegalovirus (CMV), and herpes viruses are

in several stages of development. Enzo biochem has an exclusive

antisense patent with the State University of New York, but a

number of companies are developing antisense drugs. Isis is now

in phase I clinical trials for human papilloma virus infection.

A disease thought to infect over six million women in the U.S.A..

Antisense compounds have been devised which inhibit gene tran

scription by triplex formation, mRNA translation, and cause the

breakdown of specific mRNAs. Isis has also developed antisense

compounds with their new patented "second generation" chemistry

that inhibit the ras oncogenes, specifically c-Ha-ras. These

antisense compounds were shown to be effective against cancer

cells by researchers at Isis. Similar oligonucleotides are

being developed by Microprobe of Bothwell WA. They are develop

ing nucleotide and protein drugs for the detection and treatment

of conditions such as vaginitis. Antisense compounds which have

shown great promise recently have been developed by Gilead Sci

ences. C-5 propyne pyrimidine containing antisense oligonucleo

tides are ten times more potent than other antisense compounds.

These drugs make up a significant proportion of the "designer"

drugs of modern biotechnology.

Transcription....................................#

Transcription

The ability to specifically regulate genes will aid condi

tions such as: cancer, genetic disorders, and aging. Tran

scription inhibitors are being developed and are in the very

early stages of development. Areas to be targeted for these

compounds will include oncogene specific transcription factors of

viral enhancer/promoters. Oncogene Sciences has made a commit

ment to study transcription inhibitors for anticancer therapeut

ics. A company that was formed recently, Tularik, Inc., will

look for transcription inhibitors as drugs. Steven McKnight has

formed Tularik, Inc. with Robert Tjian of Univ. of Calif., Berke

ley and David Goeddel of Genentech. Tularik, Inc. will focus on

inhibitors of transcription for these drugs. The first targets

for drugs will be viruses such as herpes viruses. Drugs which

enhance transcription of specific genes are also being developed.

Vertex, Inc. has licenesed the use of small organic molecules

from Children's Hospital Oakland which enhance the transcription

of fetal hemoglobin. Fetal hemoglobin is not normally utilized

by adult cells. It has a slightly higher affinity for oxygen

than adult hemoglobin which aids the transplacental transfer of

oxygen. The gene is not actively transcribed in the adult.

These organic molecules, one administered orally and the other

intravenously, potentiate the transcription of this silent gene

in adults. These molecule will be used to treat the hemoglobin

disorders, á-thalassemia and sickle cell anemia. Fetal hemo

globin has been shown to benefit these patients. Vertex, Inc. is

committed to rational-drug design.

Splicing.........................................#

Splicing z

Splicing is the process used by Eukaryotic cells to combine

gene segments into a functional mRNA for translation. Eukaryotic

genes are often separated on the DNA chromosome by "untranslated

regions" called Introns. To join the translated regions (the

Exons), the large RNA transcript is "spliced" to produce a func

tional mRNA for translation into protein. This process is being

targeted by a number of companies to produce a number of products

including better agricultural products and AIDS therapeutics.

For example, the alteration of the normal splicing process could

inhibit gene translation. Furthermore, the production of novel

"spliceosomes" could destroy viral RNA, such as HIV RNA. Ribo

zyme Pharmaceuticals of Denver, CO, a biotech startup company of

United States Biochemical Corp., is one company involved in this

research. They currently have are working with DowElanCo to

produce better agricultural products, such as a disease-resistant

corn and a corn which produces more oil. Innovir Laboratories of

New York, NY is cleaving target RNA with the enzyme RNAase-P

attached to specific sequences. They are currently interested in

blocking viruses and disease causing proteins.

Cell cycle.......................................#

Cell Cycle.

The process of cell division, or proliferation takes dis

crete steps. Through an ordered progression of stages a cell

divides. In these steps, the cell synthesizes new proteins, DNA,

and other macromolecules. The cell cycle is most simply divided

into the stages: G0 (G stands for gap), G1A, G1B, S (Synthesis,

DNA), G2, and M (mitosis). Most cells of an organism are in the

the G0 stage. Mitogens or growth factors move the cell out of

this stage and into the G1A stage. It is at this step that many

of the drugs aimed at transcription factors and growth factor-

associated protein kinases are founded. See the section on

cancer therapy. TGF-ás inhibit cell division in late G1 stage.

The retinoblastoma gene product and p53 are examples of tumor

suppressor genes that act at the G1/S boundry. Mutation of these

genes is associated with several malignancies. Gene therapies

based upon the introduction of a non-mutated or wild type RB or

p53 are being tried as a cancer treatment. See cancer therapy

above. Other portions of the cell cycle are being targeted by a

number of companies. See transcription above. One company spe

cifically devoted to cell cycle-based therapeutics is Mitotix,

Inc..

Biomedicine:Virology.............................#

Biomedicine: Virology:

Antiviral compounds will be highly profitable for modern

biotechnology and are under intense investigation. As already de

scribed, viruses are obligate intracellular organisms, they must

replicate in living cell. This is because they require energy

production from the cell as well as its macromolecule synthetic

machinery. Since these functions are required by the cell as

well, these functions are difficult to target for antiviral

compounds because normal cell function is disrupted. An antivir

al compound must be created which interrupts virus specific

functions. This will depend on the type of virus and often on

the specific virus. This is in contrast to anti-bacterial agents

such as penicillin or streptomycin. These agents act on compon

ents specific for bacteria and will act on many different bacte

ria. The life cycle for a virus is: adsorbance, penetration,

uncoating, replication and/or latency, packaging, and maturation

and release. These are the stages that are targeted for antivir

al compounds. Adsorbance is the step most often targeted. This

is accomplished with the induction of antibodies by vaccines, as

mentioned above. Other methods for blocking virus adsorbance

include the recent use of soluble CD4 (sCD4) to block the adsor

bance of HIV to T cells as an AIDS treatment. Replication is

also targeted for antiviral compounds. This approach is depend

ent upon the type of virus. Retroviruses, RNA viruses which

must integrate in to DNA to replicate, utilize a virus-specific

enzyme for replication. This enzyme, reverse transcriptase,

transcribes DNA from the virus's RNA. This is the target of AZT,

ddI, and ddC. Although AZT has been shown to prolong life for

AIDS patients, it has been disappointing that there is no dif

ference in the patients who have been treated before ARC (AIDS-

related complex). AZT apparently has a "limited benefit for a

limited period of time". Furthermore, a recent panel of inde

pendent experts does not recommend AZT therapy to people with

extremely low CD4 counts. Healthy individuals have CD4 counts

ranging from 800-1200 and people infected with the HIV virus have

CD4 counts in the 200-500 range. A new formulation of drugs

which also targets reverse transcriptase has been devised recent

ly by scientists at Massachusetts General Hospital that incorpo

rates 3 reverse transcriptase drugs, U-90,152. It contains all

three of the above mentioned drugs, AZT (zidovudine), ddI (diano

sine) and ddC (zalcitabine). This is very potent in the labora

tory. There was data to suggest that it may be difficult for the

virus to mutate and become resistant to this combination. Howev

er, recent reports have claimed that HIV is able to mutate after

20-30 generations in the laboratory. This type of convergence

therapy is also being developed by Merck for HIV. They are

conducting clinical trials with a two-drug combination which

utilizes the same principles. Antisense compounds are also being

used to target viruses. These drugs can be specific for mRNAs of

viruses and block the production of virus specific proteins or be

targeted toward DNA of the virus and inhibit the transcription of

specific mRNAS. Gene therapy approaches may prove to be fruitful

here as well, and some adeno-associated virus vectors with anti

sense HIV genes have been tried and have been shown to work in

vitro. Genta has an antisense drug for the treatment of acute

leukemia caused by the HTLV I virus. This has been shown to work

in mice. Isis has an antisense drug for human papilloma

viruses and others are being developed for HIV, CMV, and Herpes

viruses. The antisense drug for human papilloma virus is in

pivotal phase II clinical trials. A patent has also been issued

to them to them for Epstein-Barr virus infections. A herpes

virus that infects over 80% of the worlds population. This

antisense drug is directed at EBNA-1, a gene that is expressd in

some lymphomas, leukoplakias, and carcimonas. Gilead Sciences,

Inc. has a new powerful antisense drug which is ten times more

effective than those previously used. Abbott Laboratories of

Illinois have developed a drug for treatment of HIV infection

which targets the maturation step of the virus. HIV requires a

dimer of a protease molecule for maturation. Abbott Laborato

ries has designed a symmetrical molecule which as a high affinity

for the active site of this molecule, thus blocking maturation of

the virus (C2 inhibitor). The AIDS virus, HIV, has also been

implicated in programmed cell death, apoptosis. L. Montagnier,

the discoverer of the HIV virus, has suggested the use of anti-

apoptotic agents along with antiviral agents for the prolongation

of life in AIDS as well. These agents include: vitamin C,

vitamin E, N-acetyl-cysteine, and superoxide dismutase. Retinoic

acid, the active metabolite of Vitamin A has also been shown to

inhibit apoptosis in T cells (see selected reading).

Gene therapy approaches to the inhibition the transcription

of viral genes and the maturation of viruses are also being

attempted. Several approaches are being attempted. What seems

fruitful recently has been the targeting of antibodies to virus

products to specific intracellular locations. So far, a modified

antibody has been targeted to the endoplasmic reticulum (ER).

The ER is the intracellular organelle which begins post-transla

tional modification of proteins. An antibody directed against

gp160 of the HIV was placed in a DNA vector. Transfection of

cells with this DNA construct has been shown to inhibit matura

tion of the HIV virion. Other intracellular targets are being

investigated for this virus (and other viruses), as well. Fur

thermore, other peptides and antibodies may be found by screening

techniques such as those described in the drug discovery section.

Biomedicine:Cardiovascular drugs.................#

Biomedicine: cardiovascular drugs:

Cardiovascular drugs have been under development by modern

biotechnology companies. Transforming growth factor-ás (TGF-ás)

(Genentech:TGF-á1, Celtrix: TGF-á2, and Oncogene Sciences:TGF-

á3), are members of a family of over 18 proteins. TGF-ás have

pleotropic effects on many cell types including immune cells and

fibroblasts. They are involved in immune memory, immune suppres

sion and wound healing. TGF-ás have been shown to mediate cardi

ac protection after ischemic injury. The protective effect is

thought to be due to the inhibition of TNF (tumor necrosis fac

tor) secretion by lymphocytes after ischemic injury. Antisense

oligonucleotides (Genta) are some of the newer cardiovascular

drugs which have shown promise. Specifically, antisense oligonu

cleotides for the c-myb oncogene have been shown to inhibit

closure of the arteries after angioplasty.

Blood substitutes are being developed by Somatix. Artifi

cial blood products is one of the major new biotechnology pro

ducts of this company.

Biomedicine:Wound healing........................#

Biomedicine:Wound Healing

Wound healing is a complicated process involving the fibro

basts, epidermal cells, and the immune system. Future use of

modern biotechnology will utilize cytokines to promote wound

healing in people who cannot heal properly and to grow skin for

transplants to severe disruptions in skin integrity, such as in

burn patients. The TGF-ás are involved in would healing (Genen

tech:TGF-á1, Celtrix: TGF-á2, and Oncogene Sciences:TGF-á3).

Oncogene Sciences, Inc. is developing the use of TGF-á3 with

Pfizer, Inc. and Ciba Geigy, Limited for the treatment of healing

disorders such as oral mucositis which occurs after chemotherapy

and wound healing in aged individuals.

Drug production..................................#

DRUG PRODUCTION:

Advances in biotechnology has spurred and demanded new

methods of drug production. Bacteria have been used for years to

produce recombinant proteins for pharmaceutical use. The most

notable of these is insulin. Baculovirus systems have been

recently developed and used for the production of drugs in vitro.

Baculoviruses grow in insect cell lines which grow very rapidly

in culture. These cells are used for the production of recombin

ant proteins from eukaryotic (non-bacteria) organisms. These

cells are capable of post-translational modifications, like

glycosylation. Therefore, the recombinant protein grown in these

cells generally has a better bioactivity than those produced in

bacteria. The most recent addition for methods of drug produc

tion developed by modern biotechnology are transgenic animals

which produce pharmaceuticals in their milk. Goats, cows, and

pigs are being developed which produce specific pharmaceuticals.

Genepharming Europe BV, is developing cows that produce a human

antimicrobial protein in their milk, lactoferrin. Pharmaceutical

Proteins of Edinburg is developing transgenic sheep that will

produce human alpha-1 antitrypsin in their milk. Transgenic

goats are being developed by Genzyme Transgenics, a subsidiary of

Genzyme, that will produce CFTR in their milk. CFTR is the

defective protein in the disease cystic fibrosis. So far, only

microgram quantities can be produced in these goats. They hope

amounts suitable for clinical use can be produced within the

decade. See the drug delivery section below. Transgenic plants

are another method by which modern biotechnology products will be

produced. See the agriculture section below.

Drug delivery....................................#

Drug Delivery

Any compound conceived of or discovered by the above method

requires a delivery system to be realized as a commercial bioac

tive molecule. A drug delivery system includes the method of

application of the drug to the organism, the method of cell

uptake, and stabilization of the compound for efficient delivery.

This delivery can take the form of a virus, an antibody, a modi

fied antibody, a chemical or a selected binding peptide. Seragen

is developing fusion toxins which target activated T cells via

the IL 2 receptor. So far, this treatment will be used for

rhematoid arthritis, certain cancers (chemotherap resistant

lymphomas) type I diabetes, and HIV infection. Furthermore,

idiotype vaccines (killed MBP-reactive T cells are used to immun

ize against MS) have shown some promise and are in phase I tri

als. Derivatives of antibodies which are reduced in size are

being developed for enhanced drug delivery (Creative Biomolec

ules) and Single Chain Antigen Binding (SCA(TM)) technology is

being developed by Enzon. These smaller molecules are better

able to penetrate tumor tissues. Viral vectors have already been

used to treat disease and several studies will be undertaken very

shortly. So far, human gene therapy has involved retroviral

vectors only. For example, a crippled retrovirus with a the

adenine deaminase gene inserted in it has been used for treatment

of some cases of severe combined immunodeficiency (SCID). Future

gene therapy will most likely include the use of other vectors

such as herpes virus vectors and adeno-associated virus vectors

as well as retroviruses. An adenovirus based gene therapy has

been approved for use in cystic fibrosis. Studies are underway

to deliver drugs by transfection of blood and cells with the gene

therapy. PEGnology has been one of the most fruitful drug deliv

ery systems of the last decade. Drugs are attached to polyethy

lene glycol and this gives them better stability and solubility

properties. This has been used for IL 2, soluble CD4 (sCD4), and

many other proteins. Enzon has an orph n drug patent on PEG-

glucocerebrocidase for the treatment of Gauchers disease. Trans

dermal drug delivery is now being used to delivery of drugs

through the skin by osmosis and electric currents. The e "high-

tech" systems are showing promise for the controlled continuous

delivery of drugs.

Improvement of agricultural products.............#

Improvement of Agricultural Products:

Plants are now in a "third wave of plant biotechnology".

The "first wave" was to produce plants with improved agronomic

traits, such as disease and herbicide resistance. Kirin Brewery

of Japan has spent 2.5 million dollars for Calgene, a Campbell

soup company, to develop disease resistant potato seedlings.

Calgene has also developed BXN cotton which is resistant to the

herbicide bromoxynil. Furthermore, attempts are being made to

place antibody genes in tobacco plants at Scripps Research Insti

tute in La Jolla, California as a new form of transgenic plant

which produces its own pesticide. Antisense genes for plant

viruses are being developed as well. The bean yellow mosaic

virus (BYMV) antisense gene is hoped to protect ornamental flow

ers and legumes against the virus. Genetically modifying

agricultural products to produce bacterial toxins is one approach

to reducing the use of conventional insecticides. Bacillus

thuringiensis delta toxins have been used to transform several

crops and impart pest resistance to them. Plant genetic materi

als (PGMs) from plants resistant to disease are used to produce

new plants that are resistant to disease. Ribozyme Pharmaceu

ticals is developing a corn which is more resistant to disease

using their splicing technology. The "second wave" of plant

biotechnology was to produce altered plants with better food

processing traits, such as slowing down the ripening of tomatoes

with antisense transgenes. This was accomplished by Calgene, who

developed the "Flavr Savr tomato". Calgene has also developed a

non-antisense or co-suppression recombinant DNA method to control

tomato ripening that will be useful in many different plant

species. This method of "Ethylene Control" utilizes a DNA con

struct for the introduction of an enzyme that controls ripening.

A U.S. patent was granted to Calgene for this method of "Ethylene

control" in July of 1993. Furthermore, a corn which produces

more oil is being developed by Ribozyme Pharmaceuticals. The

"third wave" of plant biotechnology is yielding plants that

produce phamaceuticals, specialty chemicals, and biopolymers.

This is being attempted by a number of companies, including

Monsanto and Biosource Genetics Corp. Monsanto has transgenic

tobacco plants that produce à-amylase and Michigan State Univers

ity, in collaboration with Miescher Institute in Basel, Switzer

land have produced turnips which produce human à-interferon.

Future modifications of plants will include plants that use less

fertilizer, improvement of nitrogen fixation or the creation of

nitrogen fixing non-legume plants. Steps toward this goal have

been the determination of the structure of enzymes involved in

nitrogen fixation and the induction of nodules on non-nitrogen

fixing plants which may one day hold microbes capable of fixing

nitrogen, like legumes. Ornamental plants may undergo a transi

tion induced by modern biotechnology. The luciferase gene, the

gene that causes fire-flies to emit light, has been successfully

transfected into plants. This may one day lead to a new genera

tion of ornamental plants that emit light. So far, however, the

chemical substrate for luciferase.

Genetic engineering of livestock has been undertaken by a

number of companies with limited success so far. Transgenic

cattle with a leaner meat are being attempted. Genetic Engi

neering of Colorado has attempted to create cattle transgenic for

the chicken myosin gene. This has not been successful, yet.

Although the gene was inserted and the chicken gene was made, the

animal developed muscle weakness early in life and was "put down"

at a very young age.

Biological control...............................#

BIOLOGICAL CONTROL

Biological control with techniques of modern biotechnology

is being investigated for the maintenance of biodiversity, the

control of pests, and prevention of the transmission of disease

to humans. For example, recombinant vaccines have been developed

to vaccinate wild animals against the rabies virus. Biological

control of pests with infectious agents is being attempted for

vermin of agricultural products. Parasitic wasps are being

examined for the control of caterpillars which destroy a number

of crops. Fungi which infect onion worm larvae are another

example of an approach to biological control of agricultural

products. Furthermore, bacterial toxins are being investigated

for the control of insects as an alternative to insecticides (See

the improvement of agricultural products section). Biological

control of organisms in order to preserve biodiversity is now

being scrutinized in Australia to preserve the numbats, an Aus

tralian marsupial. However, this approach has reasonably been

questioned. Since this approach will sterilize red foxes and

rabbits with viruses, the fear of the escape of these organisms

from Australia and the sterilization of world populations of

these two organisms is a reasonable concern.

Marine biotechnology.............................#

MARINE BIOTECHNOLOGY

Current interests of marine biotechnology include develop

ment of fish which are resistant to disease and with desirable

growth characteristics, new treatments for fish diseases, and

diagnosis of fish illnesses. Breeding fish with desired traits

is being approached by classical genetic methods and by new

technologies like the introduction of transgenes. The release of

transgenic fish into the environment is now being considered by

scientists and environmentalist groups. The national biotech

nology center at the National Wildlife Federation is an environ

mental group that is considering this proposal. The Agricultural

Biotechnology Research Advisory Committee (ABRAC) is developing

safety standards. Treatment and diagnosis of fish diseases is an

active interest of biotechnology, particularly for domestic pro

duction of fish. Fish ponds and holding pens are used for the

farming of fish for human consumption. These environments are

unnatural and lead to the rapid dissemination of disease. There

fore, methods of early detection and treatment are required for

these environments. For example, Mirologix Biotech, Inc. is

developing detection kits and treatments for: Bacterial kidney

disease (Renibacterium salmonianrum), Furunculosis, (Aeromonas

spp.), Vibrosis (Vibrio), and Red-mouth disease (Yersinia ruck

eri).

Improvement of the environment...................#

IMPROVEMENT OF THE ENVIRONMENT:

Improvements in the environment which can be the result of

modern biotechnology will obviously include: clean water, photo

synthesis, O2 production and C02 utilization, and removal toxic

pollutants. Japan Research Development Corp. has committed $15

million over 5 years to Michigan State University for the devel

opment of microbes to improve the environment. Many other compa

nies have been involved in this research as well. Previous

successes have included genetically modified bacteria for digest

ing hydrocarbons.

Biodiversity and the maintenance and/or repair of the eco

system are of current interests to the world and the biotechnolo

gy industry as well. There have been significant setbacks re

cently, however, and these are in part due to the biotechnology

industry in the United States of America. The United States of

America hesitated at the recent summit on the "Biodiversity

Treaty" and it was not signed by the United States of America

even though 98 countries adopted it. The Clinton administration

has now signed it and it is waiting to be ratified by the senate.

The United States of America was concerned that the treaty is

merely an attempt to co-opt a technology that they already domi

nate, biotechnology. The explanation for their failure to sign

the treaty is that its uncertain compulsory licensing scheme may

defeat its own purpose, causing a greater destruction of the

current biodiversity. However, there is now a controversy about

whether to charge the West royalties for the use of PGMs (plant

genetic materials) from developing countries. This demand has

been increased recently in the wake of the biodiversity treaty.

The maintenance of biodiversity and the world ecosystems is

likely to require drastic measures which protect our biological

resources and our biotechnology industries. The Biotechnology

industry is likely to play a large role in maintaining biological

diversity as well as creating a better living environment.

The identification of a new taxol source is an example of a

recent success the biotechnology industry. Environmentalists

have been concerned that the Pacific yew tree would be wiped out

by the isolation of taxol from it. Now a new source has been

identified, the fungus Taxomyces andreanae. Cytoclonal Pharma

ceutical, Inc. has recently agreed to commercialize this form of

taxol.

ECONOMICS OF THE BIOTECHNOLOGY INDUSTRY.................#

ECONOMICS OF THE BIOTECHNOLOGY INDUSTRY

The biotechnology industry has suffered serious setbacks in

1993. This drop in stock prices for the biotechnology industry

has resulted from several blows to the industry: test results and

the political climate. Furthermore, drug prices have come under

a great deal of scrutiny and are also affected by the political

climate as well as the structure of the health care centers. The

move toward managed care networks has created large purchasers of

health care products. These large purchasers are forcing compa

nies to developed breakthrough and cost-effective products.

Test results have caused a major setback in the biotechnolo

gy industry recently. These have resulted from drugs targeting

the septic shock that can result from infection of the blood

stream after illness, trauma, or surgery. Centocor and Xoma

corporation were both developing a version of monoclonal antibod

ies to endotoxin. Endotoxin is the component gram negative

bacteria responsible for initiating septic shock. Centocor's

"Centoxin-HA-1A" and Xoma's "E " versions of these antibodies

were aimed at neutralizing the endotoxin. Both were deemed

ineffective by the FDA on January 18, 1993 for treating septic

shock. The second blow to drugs designed to treat sepsis came

with the phase III clinical results of Synergen's drug, Antril.

Synergen's stock price loss was dramatic. The price of Syner

gen's stock dropped 28 points, from 42.125 to 14.125 in one day,

February 22, 1993. Antril is Synergen's preparation of an antag

onist for interleukin 1 receptors called IL 1ra. Interleukin 1

is secreted by the immune system in response to components of

bacteria and it initiates many of the symptoms of septic shock,

such as hypotension. Administration of IL 1ra preparations, such

as Antril, were to alleviate the effects of the IL 1 induced by

the infections. Phase II clinical trials were very impressive

for Antril, treated patients exhibited 27% mortality versus 64%

for those who received the placebo. Phase III clinical trials

were very poor, however, and this sent Synergen's stock down on

February 22, 1993. Antril treated patients had a 29% mortality

versus 34% for patients who received a placebo. A detailed

chronology of Synergen's Antril failure can be found in appendix

B. Soluble interleukin 1 receptor, developed by Immunex has also

been deemed ineffective for septic shock. Xoma is in phase I

clinical trials with another product aimed at treating septic

shock, RBI-23. This compound is a recombinant version of human

BPI. BPI, or bactercidal protein, also binds IL 1 and TNF.

Therefore, it may have the effect of both inhibiting the action

of the endotoxin induced IL 1 and TNF.

The political climate has also effected the prices of bio

technology stocks. There has been an uneasiness about the

healthcare reforms that the Clinton administration will be ini

tiating. The AMEX's biotechnology index, BTK, fell to 103 in

August of 1993 from January's price of 170 and the CBOE's, BGX,

stock index fell from 162 on December 31, 1992 to 101 in August

of 1993. However, the Clinton administration allocated a 16%

increase to the National Science Foundation (NSF) and a 3.3%

increase to NIH. Together with postive fellings about the Clin

ton Administration's "Healthcare Reform", the BTK and the BGX are

recovering in October of 1993 at 134 and 130, respectively.

Drug prices are also affected by the political climate.

This in turn will naturally affect drug profitability and the

stock prices of pharmaceutical and biotechnology firms. A recent

report from the Office of Technology Assessment said that the

market failed to control drug prices. Furthermore, drug firms

have been accused of gouging the public. U.S. drug prices are

higher in the U.S.A., and the U.S. Senate has accused the indus

try of price-gouging. They have claimed that the revenues of the

pharmaceutical industry far exceed other industries and that

market pressures do not affect the prices of drugs. Obviously,

all of this affects drug prices. Despite these price criti

cisms, drugs have been shown to be the most cost-effective thera

py and pharmaceutical firms invest more in research and develop

ment than any other industry, 16.7% or their revenues. Further

more, the PMA claims there must be potential for high reward to

justify the risk that pharmaceutical companies must take. There

fore, any controls imposed should not stifle drug development

and will have to take this into consideration. The U.S. gov

ernment has supported this as well. President Clinton's health

care reform has imported no price controls for the pharmaceutical

industry. An example of the biotechnology industry controlling

its own prices has occurred for transgenic animals. There has

been an uproar recently about the prices of transgenic mice and

knock-out mice. GenPharm of Mountain view, CA was accused of

charging 10 times more for "knockout" mice than non-profit

organizations. The president of GenPharm told the National

Academy of Science recently that researchers can buy the breeding

pairs and then breed as many as they want for an annual fee of

$1000.

INFORMATION ABOUT BIOTECHNOLOGY.........................#

INFORMATION ABOUT BIOTECHNOLOGY

Keeping up with the biotechnology industry: news and servic

es. There are a number of investment newsletters available,

several of which keep track of predominately biotechnology stocks

(appendix C). For general stock analysis, "The Chartist", is

highly rated. The AgBiotech stock letter, Medical Technology

Stock Letter, and Sturza's Medical Investment Newsletter mainly

focus on medical-technology companies. Investing often has

interesting articles, but must be used with caution. For exam

ple, in January of 1993 claimed that Synergen stock "was nearing

the end of a long fall from its all time high of 75". As men

tioned above, Synergen's stock fell 28 points in one day to

14.25, with a high of 19 for the day. There are several databas

es that can be found on-line. Current Quotes and the Executive

News Service of CompuServe Information Service (CIS) are very

useful for tracking the daily activity of biotechnology stocks.

Several folders can be made to track biotechnology news for

inventions, results, and company reports. Furthermore, Smart

Scans and Knight-Ridder's Knowledge Index can be found on CIS.

Knight-Ridder's Dialog, a more sophisticated database, has

several files which are useful for obtaining specific information

on biotechnology. See appendix B for a list of useful databases

on Dialog. Mead Data Central of Dayton, Ohio, which offers Lexis

and Nexis services, was to allow individual users access in 1991.

GEnie, the computer service of General Electric also offers

several useful databases similar to CIS. Furthermore, they offer

a gate to the Dow Jones News/Retrieval service. The Prodigy

service can be used for retrieving stock quotes.

INVESTING IN BIOTECHNOLOGY..............................#

INVESTING IN BIOTECHNOLOGY

Investing in the biotechnology industry can be very profit

able. In the last couple of years there have been a large number

of "winners" in the market. Immunex, Oncogene Sciences, Cellpro,

and Biogen are all example of this. Immunex is now part of

American Cyanamid after a merger with the Lederle Oncology Corpo

ration in June of 1993. The recent fall of the stock price of

several biotechnology companies, however, has introduced the

possibility of loosing money by investing in biotechnology. For

example, the fall of Synergen's stock by 70% in one day was an

incredible unpredictable loss. Obviously, care must be taken

when investing in biotechnology today. The establishment and

maintenance of a successful personal portfolio of stocks of

modern biotechnology companies will require intelligence and

thought. This can be done by being informed of the goals of

individual biotechnology companies and their approaches to devel

oping and producing their biotechnology goals. Discount brokers

can be found on most large computer services, such as Quick and

Reilly and Spear Securities on CIS. Alternatively, one can

invest in biotechnology investment funds. One fund which has

done well is Global Health Sciences Fund of Denver, CO. Through

much of the slump in biotechnology prices described above, they

showed a $0.00/share loss. They can be reached at (800) 528-8765

or (303) 930-6521.

SELECTED READING........................................#

SELECTED READING:

Eisenberg, RS. 1992. Genes, patents, and product development.

Science 257:903-918.

Marshall, E. 1991. The patent game: Raising the ante. Science

253:20-24.

Kiley, TD. 1992. Patents on random complementary DNA fragments?

Science 257:915-918.

Adler, RG. 1992. Genome Research: Fulfilling the public's expec

tations for knowledge and commercialization. Scien e 257 :908-

914.

Amato, I. 1992. Speeding up a chemical game of chance. Science

257: 1992.

Anderson, C. 1993. Clinton's technology policy emerges. Science

259: 1244.

Science. May 28, 1993. AIDS: The unanswered questions. Science

260:1254-1285.

Erickson, J. et al. 1990. Design, Activity, and 2.8 crystal

structure of a C2 symmetric inhibitor complexed to HIV-1 pro

tease. Science 249:527-534.

Vagelos, PR. 1991. Are perscription drug prices high. Science

252: 1080-1084.

Trends in Biotechnology

Saiki, RK, Gefland, DH, Stoffel, S, Scharf, SJ Higuchi, R, Horn,

GT, Mullis, Erlich, HA. 1988. Primer-directed enzymatic amplifi

cation of DNA with a thermostable DNA polymerase. Science

239:487-494.

Koff, WC and Hoth, DF. 1988. Develoment and testing of AIDS

vaccines. Science 241:426-432.

Geisow, MJ. 1993. Aching for approval, hoping for harmony -

biotech product regulation. Trends in Biotechnology 10:107-110.

Liu, DT-Y. 1993. Glycoprotein pharmaceuticals:scientific and

regulatory considerations, and the US Orphan Drug Act. Trends in

Biotechnology 10:114-120.

Balter, M. 1991. How Europe regulates its genes. Science

252:1366-1368.

Friden, PM et al. 1993. Blood-Brain Barrier penentration in Vivo

activity of and NGF conjugate. Science 259:373-377.

Rosen, DR et al. 1993. Mutations in Cu/Zn superoxide dismutase

SELECTED READING (CONTINUED):

gene are associated with familial amyotrophic lateral sclerosis.

Gibbs, WW. 1993. Try, Try Again: Making antibodies more useful by

making them more human. Scientific American 269:101-103.

Kohl, NE et al. 1993. Selective inhibition of ras-dependent

transformation by a farnesyltransferase inhibitor. Science

260:1934-1937.

James, GL, 1993. Benzodiazepine peptidomimetics: Potent inhibi

tors of ras fanesylation in animal cells. Science 260:1937-1942.

Burk, DL, Barovsky, K, Monroy, GH. 1993. Biodiversity and bio

technology. 1993. Science 260:1900-1901.

Gougeon, M-L and L Montagnier. 1993. Apoptosis and AIDS. Science

260:1269-1270.

Ketajima, I. et al. 1992. Ablation f transplanted HTLV-I Tax-

transformed tumors in mice by antisense inhibition of NF-KB.

Science 258:1792-1796.

Nature 359:67. Antisense c-myb for athleroscerosis.

Hyde, SC. 1993. Correction of the ion transport defect in cystic

fibrosis transgenic mice by gene therapy. Nature 362:250.

Anderson, WF. 1992. Human gene therapy. Science 256:808-814.

Chatterjee, S et al. 1992. Dual-target inhibition of HIV-1 in

Vitro by means of an adeno-associated virus antisense vector.

Science 258:1485.

Culver, KW et al. 1992. In Vivo gene transfer with retroviral

vector-producer cells for treatment of experimental brain tumors.

Science 256:1550.

Trail, PA et al. 1993. Cure of Xenografted human carcinomas by

BR96-Doxorubicin immunoconjugates. Science 261:212-215.

Rabizadeh, S, J Oh, L-t Zhong, J Yang, CM Bitler, LL Butcher, DE

Bredesen. 1993. Induction of apoptosis by the low-affinity NGF

receptor. Science 261:345.

Anderson, WF. 1992. Human Gene Therapy. Science 256:808-814.

Golumbek, PT, AJ Lazenby, HI Levitsky, LM Jaffee, H KArasuyama, M

Baker, DM Pardoll. 1991. Treatment of established renal cancer by

tumor cells engineered to secrete interleukin 4. Science

254:713.

SELECTED READING (CONTINUED):

Iwata, M, M Mukai, Y Nakal, and R Iseki. 1992. Retinoic acids

inhibit activation-induced apoptosis in T cell hybridomas and

thymocytes. J. Immunol. 149:3302-3308.

Pietsch, T, U Kyas, U Steffens, E Yakisan, MR HAdam, W-D Ludwig,

K Zsebo, and K Welte. 1992. Effects of human stem cell factor (c

kit ligand) on proliferation of myeloid leukemia cells: Heterero

geneity in response and synergy with other hematopoietic growth

factors. Blood 80:1199-1206.

Betaseron Study. April 1993. Neurology.

Lehner, T, LA Bergmeier, C Panagiotidi, L Tao, R Brookes, LS

Klavinskis, P Walker, J Walker, RG Ward, L Husaain, AJH Gearing,

adn SE Adams. Induction of mucosal and systemic immunity to a

recombinant simian immunodeficiency viral protein. Nature

258:1365-1369.

Mervis, J.. 1993. Regulations go Swimmingly. Science 261:542.

Stone, R.. 1993. Biotech firm licenses taxol-making fungus.

Science 261:543.

Stierle, A., G. Strobel, D. Stierle. 1993. Taxol and Taxane

production by Taxomyes andreanae, endophytic fungus pacific yew.

Science 260:214.

Nijn, I, L das Neves, A van Kammen, H Franssen, and T Bisseling.

1993. Nod factors and nodulation in plants. Science 260:1764.

Palca, J. 1992. Testing target date looms, but will the vaccines

be ready. Science 257:1472.

Travis, J. Putting antibodies to work inside cells. Science

261:1113.

McGaughey, W.H. and M.E. Whalon. 1992. Managing insect resist

ance to Bacillus thuringiensis toxins. Science 258:1451.

Morell, V. 1993. Australian pest control by virus causes concern.

Science 261:683.

Weiner, H.L., G. A Mackin, M. Matsui, E.J. Orav, S.J. Khoury,

D.M. Dawson, D.A. Hafler. 1993. Double-blind pilot trial of oral

tolerization with myelin antigens in multiple sclerosis. Science

259:1321.

Zhang, J., R. Medaer, P. Stinissen, D. Hafler, and J. Raus. 1993.

MHC-restricted depletion of human myelin basic protein-reactive T

cells by T cell vaccination. Science 261:1451.

Hsieh, C.-S., SE Macatonia, CS Tripp, SF Wolf, A O'Garra, KM

Murphy. 1993. Development of TH1 CD4+ T cells through IL-12

produced by Listeria-induced macrophages. Science 260:547-549.

Cohen, J. T cell shift: Key to AIDS therap ? Science 262:175-

176.

APPENDIX A..............................................#

APPENDIX A

The Overlapping Stocks of the CBOE and the AMEX are:

Amgen (AMGN)

Biogen (BGEN)

Centocor, Inc. (CNTO)

Chiron (CHIR)

Cytogen Corp. (CYTO)

Enzon, Inc. (ENZN)

Gensia Phamaceuticals (GNSA)

Genzyme Corp. (GENZ)

Greenwich Pharmaceuticals Inc. (GRPI)

*Immunex (IMNX)

Liposome Co. Inc. (LIPO)

Synergen (SYGN)

Xoma (XOMA)

*Immunex has been replaced by Immune Response Corporation on the

AMEX due to a merger with American Cyanamid.

The AMEX's Biotechnology Index

BTK: Total Capitalization as of June 2, 1993 was 91.8 million.

Amgen (AMGN)

Genzyme Corporation (GENZ)

Biogen (BGEN)

Immune Response Corporation (IMNR)

Synergen, Inc. (SYGN)

Enzon, Inc. (ENZN)

Xoma Corporation (XOMA)

Gensia Pharmaceuticals, Inc. (GNSA)

Cambridge Biotech Corp.

Liposome Company, Inc. (LIPO)

Centocor, Inc. (CNTO)

Chiron Corp. (CHIR)

Scios Nova, Inc. (SCIO)

Cytogen Corp. (CYTO)

Greenwich Pharmaceuticals, Inc. (GRPI)

APPENDIX B..............................................#

APPENDIX B

The following are quotes from the Denver Post concerning the fall

of Synergen's stock price:

January 19, 1993

BIOTECH STOCKS WOBBLY:Synergen bounces on Centocor news.

January 28, 1993

HOAX POUNDS BIOTECH STOCKS:Synergen shares plummet after false

drug-test report.

"One person's hoax, based in impatience or perhaps greed,

has sent the entire biotech industry reeling and the stock of

Boulder-based Synergen Inc. plunging"

"...on Tuesday, someone identifying himself as a doctor

involved n Synergen's study phoned in phony results to a medical

newsletter. Calling himself a physician from UCLA, he said the

drug known a Antril simply didn't work."

"While the report was'nt true, it was enough to sent Syner

gen's stock dropping more than $6 per share."

""Unfortunately, rumors of this sort no matter how specious

they may be are impossible to refute definitively, especially

when they're in such a vulnerable period"......."

""These rumors are illogical and spurious. The greatest

probability remains that the results (of Antril tests) will be

very good.""

.."The mess started Tuesday (1/26) when Evan Sturza of

Sturza's Medical Investment Letter received a call from a "Dr.

Miller", who claimed to have participated in the University of

California at Los Angeles arm of the study of Antril, Synergen's

sepsis drug.""

February 18, 1993

SYNERGEN NET LOSS SURGES

"Synergen Inc., a Boulder-based biopharmaceutical company,

reported more than a 1,000 percent increase in net loss for the

fourth quarter ....."

February 22, 1993

SYNERGEN STOCK PLUNGES 70%:Weak drug price sinks NASDAQ

APPENDIX C..............................................#

APPENDIX C

DIALOG DATABASES FOR BIOTECHNOLOGY INFORMATION

BIOBUSINESS: Covers current and retrospective biotechnology

information for business professionals, Fi e number 285, 1985-

present.

BIOCOMMERCE ABS AND DIRECTORY: Abstract records and company

profiles of the biotechnology business, Fi e number 286, 1981-

present.

BIOTECHNOLOGY ABSTRACTS: Coverage of biotechnology publications,

File 357, 1982-present

CLAIMS/REASSIGNMENT: Patents that have been reviewed by the

government and have been reassigned, File number 123.

DERWENT BIOTECHNOLOGY ABSTRACTS: File numbers 350 and 351.

DRUG INFORMATION FULLTEXT (DIF):File number 229. Brief descrip

tions of all new drugs approved by the FDA. It corresponds to

AHFS drug information and the Handbook on Injectable drugs publi

cations.

EMBASE: File numbers 72 (1974-present), 73 (1985-present), 272

(selected records from 8 weeks of 1989).

INVESTEXT: Information about companies, industry, geographic

reports etc , File numbers 545 (1982-present), 277 (1988-

present).

IMSWORLD R&D FOCUS: Latest Scientific and commercial developments

in international pharmaceuticals, File number 445.

JAPIO: Japanese patents, File number 347

PATENTS: Full text of patents, File number 654.

PATFUL: United States of America Patents, three files: 654

(1990), 653 (1980-1989) and 652 (1971-1979).

PHIND: Pharmaceutical and healthcare industry news database,

agriculture is covered as well, AGROW and Animal Pharm., File

number 129.

PREDICASTS: Newsletters classified by the industry, it includes

biotechnology, File numbers: 16 (1972-present), 216 (1988-1990),

636 (1988-present).

UNLISTED DRUGS: File Number 140.

APPENDIX C (CONTINUED):

CompuServe Databases

DISCLOSURE

VALUE-LINE

GEnie Databases

VESTOR

Dow Jones/News Retrieval

SHAREWARE...............................................#

INVESTMENTS IN BIOTECHNOLOGY IS SHAREWARE:

The author has a Ph.D. in Microbiology/Immunology and ex

pects a $30.00 fee for use of this material. Its last update was

October 15, 1993. Register your copy by sending $30.00 to P.O.

Box 18978, Denver, CO 80218-0978. The institutional and corpo

rate rate for 10 or more copies is $20.00/copy. Copyright, 1993.

It is planned that this file will be updated frequently. There

is no charge for updates of the same whole number. Updates will

carry a $15.00 charge. The author can be reached on CIS at

71240,2762.

REGISTRATION............................................#

REGISTRATION OF INVESTMENTS IN BIOTECHNOLOGY Rel 1.63

REGISTRATION : Investments in biotechnology is being distributed

on a SHAREWARE principle. Each individual user is responsible

for the registration of their copy if they decide to keep and use

it.

SEND MONEY ORDER OR CHECK TO:

P.O. Box 18978

Denver, CO 80218-0978

TOTAL*

INDIVIDUAL (1-9 COPIES): $30.00 EACH _____ COPY(IES) ______

ORGANIZATION (10+ COPIES):$20.00 EACH _____ COPIES ______

* A disk can be obtained for an additional $5.00. A bound print

out can be obtained for an additional $20.00.

INDEX...................................................#

INDEX

Abbott, 13

Abbott Laboratories, 38

ABC, 4

Acquired immunodeficiency syndrome, 3

Actimmune, 3

Activase, 3

Acute leukemia, 37

Adenine deaminase, 42

Adeno-associated virus vectors, 37, 42

Adenovirus, 42

Adhesion molecules, 19

Adhesion receptor, 19

Adhesion receptors, 29

Adjuvant, 17, 18

Adsorbance, 36

Adult hemoglobin, 33

Aeromonas spp., 46

Affymax, 10

AgBiotech stock letter, 51

Aged, 40

Aging, 33

Agricultural, 45

Agricultural Products, 42

Agronomic traits, 42

AIDS, 3, 13, 15, 16, 18, 36, 38

AIDS treatment, 16

AIS MicroCELLector, 30

Alkermes, 25

Allergens, 18

Allergic, 18

AllerVAX, 18

Allograft rejection, 19

Alpha-1 antitrypsin, 40

Alpha-1 Biomedical, 16

ALS, 25, 26

American Cyanamid, 53, 58

American Stock Exchange, 4

AMEX, 4, 5, 50, 58

Amgen, 23, 26, 31

Amgen (AMGN), 58

Amyotrophic lateral sclerosis, 23, 25

Angioplasty, 39

Antagonist, 49

Antagonists, 28

Anti-apoptotic agents, 38

Anti-bacterial, 36

Antibodies, 13, 14, 15, 16, 21, 25, 26, 36, 38, 41

Antibody, 13, 14, 15, 30, 38, 41

Antibody gene, 43

Anticancer therapeutics, 33

Antimicrobial, 40

Antisense, 31, 32, 37, 39, 43

Antisense drugs, 31

Antisense oligonucleotides, 39

Antisense patent, 32

Antiviral, 35, 36

Antiviral agents, 38

Antril, 49

APACHE III, 8

Apache III (TM) risk model, 8

APACHE III International Database, 8

APACHE III method, 8

APACHE III model, 8

APACHE method, 8

Apoptosis, 25, 26, 38

Applied Immune Sciences, 30

Armed service, 17

Arteries, 39

Artificial blood, 39

Association of Biotechnology Companies, 4

Atherosclerosis, 31

Autoimmune diseases, 19

AZT, 36, 37

B cell, 21

B cells, 21

B7, 19, 29

B7 ligand, 19, 29

Bacillus Calmette-Guerin, 18

Bacteria, 36, 40, 47

Bacterial kidney disease, 46

Bacterial toxins, 45

Baculovirus, 17, 40

Baculoviruses, 40

BBB, 24, 25

BCG, 18

BDNF, 20, 26

Bean yellow mosaic virus, 43

Berlex, 23

Betaseron, 23, 24

BGX, 4, 50

BIO, 4, 5

Biocine, 17

Biodiversity, 45, 47

Biodiversity Treaty, 47

Biogen, 53

Biogen (BGEN), 58

BIOLOGICAL CONTROL, 45

Biological diversity, 47

Biopolymers, 44

Biosource Genetics Corp, 44

Biotechnology, 12

Biotechnology index, 50, 58

Biotechnology Industry Organization, 4

Biotechnology stock index, 4

BioTropin, 3

Blood, 39

Bone marrow transplantation, 31

BPI, 49

Bradycor, 8

Brain derived neurotrophic factor, 26

Brain lesions, 24

Brain trauma, 25

Brain tumors, 23, 25

Breast cancer, 21, 31

Breast cancers, 3

Bristol-Myers Squibb, 18

Bromoxynil, 43

BTK, 5, 50, 58

BTX, 4

BXN, 43

BYMV, 43

C-5 propyne pyrimidine, 32

C-Ha-ras, 32

C-myb, 39

C02 utilization, 46

C2 inhibitor, 38

Cachectin, 22

Calgene, 42, 43

Cambridge Bioscience, 17

Cambridge Biotech Corp., 58

Cambridge Neuroscience, 25

Campbell soup company, 42

Cancer, 15, 20, 27, 31, 32, 33

Cancer cells, 27

Cancer therapy, 14, 26, 31

Cancer treatment, 29

Cancers, 14, 41

Carbohydrate, 17

Carbohydrates, 17

Carcimonas, 37

Cardiac, 39

Cardiovascular, 31, 39

Cardiovascular drugs, 39

Cats, 18

CATVAX, 18

CBOE, 4, 5, 50, 58

CD2, 19

CD28, 19, 29

CD34, 30

CD34+, 23, 31

CD34+ cells, 21

CD4, 16, 19, 36

CD5, 19

CD8, 19

Cell-Sci, 16, 23

Cellpro, 53

Cellpro

Inc., 30, 31

Cellular immune response, 16

Cellular immunity, 17

Celtrix, 23, 39, 40

Centocor, 48

Centocor

Inc. (CNTO), 58

Centoxin-HA-1A, 48

Central nervous system, 24

Cephalon, 25

CEPRATE, 30

Cetus, 11

Cetus

Corp., 29

CFTR, 41

Chemotherapeutic, 27, 31

Chemotherapy, 23, 31, 40

Chicago Board Options Exchange, 4

Chicken, 44

Chicken myosin, 44

Children's Hospital Oakland, 33

Chiron, 17

Chiron

Corp, 29

Chiron (CHIR), 58

Chiron Corp., 23

Chiron Corp. (CHIR), 58

Cholera toxin, 18

Ciba Geigy

Limited, 40

Ciliary neurotrophic factor, 25

CIS, 51, 52, 53

Clinical trials, 7, 18

Clinton administration, 50

Cluster of differentiation, 30

CMV, 32, 37

CNTF, 6, 20, 25, 26

Co-suppression, 43

Colon cancer, 21

Colony stimulating factor, 21

Colorado, 44

Column, 30

Combined vaccine, 16

CompuServe, 61

CompuServe Information Service, 51

Convergence therapy, 37

Cortech, 8

Cotton, 43

Cows, 40

Creative Biomolecules, 41

CTLA4Ig, 19, 29

Culture, 40

Current Quotes, 51

Cyclosporin A, 18

Cystic fibrosis, 41, 42

Cytogam, 13

Cytogen, 15

Cytogen Corp. (CYTO), 58

Cytokine, 14, 20, 21, 22, 25

Cytokine combination, 23

Cytokine combinations, 23

Cytokines, 20, 21, 22, 23, 25, 39

Cytomegalovirus, 13, 32

Cytotoxic drugs, 14

Cytotoxic T cell, 29

Cytotoxic T cells, 19, 21, 29

Cytoxan, 31

Database, 52

Databases, 52, 60, 61

DdC, 36, 37

DdI, 36, 37

Deliver drugs, 42

Delivery system, 41

Denver Post, 59

Derivative, 41

Diabetes, 3, 14, 41

Diagnosis, 12, 45

Diagnostic reagents, 28

Dialog, 52, 60

Diamond v. Chakrabarty, 5

Dianosine, 37

DISCLOSURE, 61

Discount brokers, 53

DNA, 34

DNA construct, 43

Dogfish, 11

Dow, 5

Dow Jones News/Retrieval service, 52

Dow Jones/News Retrieval, 61

DowElanCo, 34

Drug, 41

Drug delivery, 41, 42

Drug development, 50

Drug discovery, 10

Drug prices, 50

DRUG PRODUCTION, 40

Drugs, 39

Dupont, 5

E5, 48

EBNA-1, 37

EBV, 29

ECONOMICS, 48

Ecosystem, 47

Ecosystems, 47

Edinburg, 40

EGF, 20

Electric current, 42

Endoplasmic reticulum, 38

Endotoxin, 48, 49

ENVIRONMENT, 46

Enzo biochem, 32

Enzon, 10, 41, 42

Enzon

Inc. (ENZN), 58

Enzymes, 44

Eosinophil, 22

Epidermal cells, 39

EPO, 23

Epstein-Barr virus, 29, 37

Equal dollar weighted, 5

ER, 38

Erthyropoeitin, 23

Ethylene Control, 43

Eukaryotic, 40

Executive News Service, 51

Exons, 34

Farnesyl group, 28

Fel D I, 18

Fertilizer, 44

Fetal hemoglobin, 33

Fetus, 17

FGF, 20

Fibrobasts, 39

Fibroblasts, 23, 39

First to file, 5, 6

First to invent, 6

Fish, 45

FISHing, 12

FK506, 18

Flavr Savr tomato, 43

Flowers, 32

Food processing, 43

Four Corners Flu, 12

Free radicals, 25

Furunculosis, 46

Fusion toxins, 14, 20, 41

Future gene therapy, 42

G-CSF, 23, 31

Gancyclovir, 25

Gauchers disease, 42

GEMS(TM) discovery system, 11

Gene therapy, 3, 30, 37, 38, 42

Genentech, 3, 4, 15, 17, 23, 33, 39, 40

Genentech

Inc., 28

Genepharming Europe BV, 40

General Electric, 52

Genetic disorders, 33

Genetic engineering, 14, 31, 44

Genetic Therapy

Inc., 21

Genetically, 47

GEnie, 52, 61

GenPharm, 15, 51

Gensia Phamaceuticals (GNSA), 58

Gensia Pharmaceuticals

Inc. (GNSA), 58

Genta, 37, 39

Genzyme, 41

Genzyme

Inc., 13

Genzyme Corp. (GENZ), 58

Genzyme Corporation (GENZ), 58

Genzyme Transgenics, 41

Gilead Sciences, 32

Gilead Sciences

Inc., 37

Global Health Sciences Fund, 53

Glucocerebrocidase, 42

Glucocorticoids, 20

Glycosylation, 40

GM-CSF, 23, 31

GOALS, 2

Goats, 40, 41

Gp120, 16, 17, 18

Gp120 vaccine, 17

Gp160, 16, 17, 18, 38

Gp160-vaccinia, 18

Graft rejection, 19, 29

Grafts, 19, 29

Gram negative bacteria, 48

Granulocyte macrophage colony stimulating factor, 31

Granulocyte-colony stimulating factor, 31

Granulomatous, 3

Greenwich Pharmaceuticals

Inc. (GRPI), 58

Greenwich Pharmaceuticals Inc. (GRPI), 58

Growth factor receptors, 27

Growth hormone, 3

Hantavirus, 12

Healthcare Reform, 50

Healthcare reforms, 50

Hematopoietc stem cells, 30

Hematopoietic stem cells, 21, 30

Hemoglobin, 33

HER-2, 3

Herbicide, 43

Herpes Simplex Virus, 25

Herpes virus, 37, 42

Herpes viruses, 32, 33, 37

Heterologous antisera, 13

HGP30, 16, 17

HIV, 13, 14, 15, 16, 17, 19, 34, 36, 37, 38, 41

HIVIG, 13

Hoffman-LaRoche, 11

HSV-tk, 25

HTLV I, 37

Human ciliary neurotrophic factor, 6

Human genome, 12

Human immunodeficiency virus, 15

Humanized antibodies, 14, 15

Humoral immune responses, 16

Humoral immunity, 18

Hydrocarbons, 47

HyperGam + CF, 13

Hyperimmune globulin, 13

Hypotension, 49

IBA, 4

IDEC Pharmaceuticals, 15

Idiotype, 14, 41

IFN-á1b, 23

IgE, 21

IGF, 20

IGF-1, 3

IL 1, 49

IL 1ra, 49

IL 2, 20, 21, 22, 42

IL 2 receptor, 19

IL 3, 23

IL 4, 21

Illness, 48

Immune globulin, 13

Immune memory, 23, 39

Immune Response Corporation, 15, 58

Immune Response Corporation (IMNR), 58

Immune responses, 19

Immune suppression, 23, 39

Immune system, 39

Immunex, 31, 53, 58

Immunex (IMNX), 58

Immuno AG, 17

Immunogen, 15, 18

ImmunoLogic Pharmaceutical Corp., 18

Immunology, 15

Immunotherapy, 27, 29

In Utero, 13

In vitro, 28

Index options, 4

Industrial Biotechnology Association, 4

Infants, 13

INFORMATION, 51

Innovir Laboratories, 34

Insect cell lines, 40

Insecticides, 45

Insulin, 3, 40

Insulin growth factor-1, 3

Integrate, 36

Intellectual Law Association, 5

Interferon-ç, 22

Interferons, 20

Interleukin 1, 20, 49

Interleukin 10, 22

Interleukin 12, 22

Interleukin 13, 22

Interleukin 2, 20, 22

Interleukin 3, 21

Interleukin 4, 21

Interleukin 5, 21

Interleukins, 20

Intracellular receptors, 28

Introns, 34

Investing, 51, 53

Investment funds, 53

Ischemic, 39

Ischemic heart injury, 23

Ischemic injury, 25

Isis, 32, 37

Japan Research Development Corp., 46

Kidney cancer, 21

Kirin Brewery, 42

Knight-Ridder, 52

Knock-out mice, 51

Knowledge Index, 52

Lactoferrin, 40

LAI, 17

LAK, 20

Leaner meat, 44

Lederle Oncology Corporation, 53

Legumes, 43, 44

Leukemia, 28

Leukoplakias, 37

Lexis, 52

LFA 1, 19

Ligand Pharmaceuticals, 28

Ligands, 28

Liposome Co. Inc. (LIPO), 58

Liposome Company

Inc. (LIPO), 58

Livestock, 44

Lou Gehrig's disease, 6, 23, 25

Luciferase, 44

Lyme disease, 18

Lymphocytes, 13, 27

Lymphokine activated killer, 20

Lymphoma, 31

Lymphomas, 14, 37, 41

Lymphotoxin, 22

Magnetic resonance imaging, 24

Malignancies, 28

Mammalian, 16, 17

Managed care networks, 48

MARINE, 45

Marsupial, 45

Maturation, 38

Maturation and release, 36

MBP, 24

Mead Data Central, 52

Medi488, 13

Medical imaging, 15

Medical Technology Stock Letter, 51

MedImmune, 13, 18

Melanomas, 21

Merck, 37

Merck Research Laboratories, 27

Michigan State University, 44, 47

Microbes, 44, 47

MicroGeneSys, 17

Microgram, 41

Micromolar, 28

Microprobe, 32

Miescher Institute, 44

Milk, 40, 41

Mirologix Biotech

Inc., 46

MN, 17

Molecular surgery, 25

Monoclonal, 13

Monoclonal antibodies, 13, 14, 15, 48

Monoclonal antibody, 13, 30

Monsanto, 44

MRI, 24

MRNA, 32, 34

MS, 14, 19, 23, 24, 41

Mucosal immunity, 18

Multi-CSF, 21

Multikine, 23

Multiple drug resistance, 27

Multiple sclerosis, 23

Muscle, 44

Mutate, 17

Mutation, 28

Myelin basic protein, 24

Myeloma, 13

N-acetyl-cysteine, 38

National Academy of Science, 51

National biotechnology center, 46

National Institutes of Health, 6, 21

National Science Foundation, 50

National Wildlife Federation, 46

Neozyme II, 13

Nerve growth factor, 25

Nervous system, 1

Neupogen, 31

Neuroleukin, 20

Neurological, 24

Neurological defects, 25

Neuron, 25

Neurons, 25, 26

Neutralizing antibodies, 16, 28

Newsletters, 51

Nexis, 52

NGF, 20, 25

NIH, 6, 50

Nitrogen fixation, 44

Nitrogen fixing, 44

Nodules, 44

Non-Hodgkin, 31

Non-legume, 44

North American Biologicals

Inc., 13

Novelty, 5

NSF, 50

Nucleotide, 32

Numbats, 45

O2, 46

Office of Technology Assessment, 50

Oligonucleotides, 11, 32, 39

Oncogene, 28, 30, 32, 39

Oncogene Science, 28

Oncogene Sciences, 11, 12, 23, 33, 39, 40, 53

Oncogene Sciences

Inc., 40

Oncogene specific transcription, 33

Oncogenes, 27, 30

Oncomouse, 5

Oncoproteins, 14

Onyx Pharmaceuticals, 29

Oral mucositis, 31, 40

Oral tolerance, 24

Organelle, 38

Organisms, 40

Ornamental flowers, 43

Ornamental plants, 44

Orphan drug, 5

Orphan drug patent, 42

Orphan drugs, 4

Osmosis, 42

Ovarian, 31

P-glycoprotein, 27

P105, 28

P17, 16

P53, 26, 28, 29

Packaging, 36

Papilloma virus, 32, 37

Papilloma viruses, 37

Parasite, 22

Parasitic wasps, 45

Parvovirus, 18

Patent infringements, 4

Patenting process, 4

Pathogens, 13

PCR, 11, 12

PEG, 42

PEGnology, 42

Penetration, 36

Penicillin, 36

Peptides, 17, 25

Peripheral nerve, 25

Perkin Elmer, 11

Perkin-Elmer, 12

Pesticide, 43

Pfizer

Inc., 40

PGMs, 43, 47

Phamaceuticals, 44

Pharmaceutical, 40, 50

Pharmaceutical firms, 50

Pharmaceutical industry, 50

Pharmaceutical Manufacturers Association, 4

Pharmaceutical Proteins, 40

Pharmaceuticals, 40

Phase I, 7, 31, 32

Phase II, 7, 18, 25, 26, 31, 37, 49

Phase III, 7, 49

Photosynthesis, 46

Pigment, 32

Pigs, 40

Placebo, 26, 49

Plant, 43

Plant genetic materials, 43, 47

Plant viruses, 43

Plants, 41, 42, 44

PMA, 4, 50

Political climate, 49, 50

Pollutants, 46

Polyclonal, 13

Polyclonal antibodies, 13

Polyclonal antibody, 13

Polyethylene glycol, 42

Polymerase chain reaction, 11

Portfolio, 53

Post-translational, 28, 40

Potato seedlings, 43

Power of a test, 8

Pre-clinical, 7

Pregnant, 13, 17

President Clinton's health care reform, 50

Price weighted, 5

Prices, 51

Primitive stem cells, 21

Prodigy, 52

Programmed cell death, 25, 38

Promega, 11

Promoter, 33

Prophylaxis, 13, 14

Protease, 38

Protein Design Labs, 15

Proto-oncogenes, 30

Pulomzyme, 3

Quick and Reilly, 53

Radicals, 25

Ragweed, 18

Ras, 14, 30

Ras gene superfamily, 29

Ras oncogene, 27, 28

Ras oncogenes, 32

RBI-23, 49

RBP, 28

Receptors, 28

Recombinant DNA method, 43

Recombinant protein, 18, 40

Recombinant proteins, 40

Recombinant vaccine, 18

Red-mouth disease, 46

Regeneron, 6, 25, 26

REGISTRATION, 63

Rejection, 14, 19, 29

Relapsing-remitting MS, 24

Renal cancer, 21

Renibacterium salmonianrum, 46

Replacement cell therapy, 30

Replicate, 36

Replication, 36

Replication and/or latency, 36

Repligen, 17

Respiratory syncitia virus, 13

Retinoblastoma protein, 28

Retinoic acid, 38

Retroviral vectors, 42

Retrovirus, 21, 42

Retroviruses, 25, 31, 36, 42

Revenues, 50

Reverse transcriptase, 36

Rhematoid arthritis, 14, 41

Rheumatoid arthritis, 19

Ribozyme Pharmaceuticals, 34, 43

Ripening, 43

Risk models, 8

RNA, 34

RNA viruses, 36

RNAase-P, 34

Sargramostim, 31

SCA(TM), 41

SCD4, 36, 42

SCF, 20, 23, 31

SCID, 42

Scios Nova

Inc. (SCIO), 58

Scotgen Biopharmaceuticals, 15

Scripps Research Institute, 43

Second generation" chemistry, 32

Second messengers, 27

SELECTED READING, 54, 55, 56

Selectide, 10

Sepsis, 22, 49

Septic shock, 14, 20, 22, 48, 49

Seragen, 14, 19, 41

Severe combined immunodeficiency, 42

SF-2 strain, 17

SH2, 27

SH3, 27

SHAREWARE, 62

Sheep, 40

Sickle cell anemia, 33

Signal transduction, 19, 29

Single Chain Antigen Binding, 41

SIRS, 8

SIV, 18

Skin, 39

Skin integrity, 39

Small molecule therapeutics, 29

SmartScans, 52

Soluble CD4, 36, 42

Soluble receptors, 28

Somatix, 39

Spear Securities, 53

Spliced, 34

Spliceosomes, 34

Splicing, 34, 43

Squalamine, 11

Stanford, 6

State University of New York, 32

Statistical methods, 8

Stem cell, 31

Stem cell factor, 20, 23, 30

Stem cells, 23, 30

Stimulon with QS-21, 17

Stock index, 50

Stock quotes, 52

Stratagene, 10

Streptomycin, 36

Sturza's Medical Investment Newsletter, 51

Superoxide dismutase, 25, 38

Suppressor T cells, 24

Surgery, 48

Synergen, 6, 26, 49, 51, 53

Synergen

Inc. (SYGN), 58

Synergen (SYGN), 58

Syntex, 26

Systemic inflammatory response syndrome, 8

á-interferon, 23, 24

á-thalassemia, 33

T cell, 19, 21, 24, 29

T cell growth factor, 21

T cell receptors (TCR), 29

T cell subpopulations, 21

T cells, 16, 19, 21, 24, 29, 36, 38

Taxol, 10, 31

TGF-á, 20

TGF-á1, 3, 23, 39, 40

TGF-á2, 23, 39, 40

TGF-á3, 23, 31, 39, 40

TGF-ás, 22, 23, 39, 40

TGF-à, 20

The Chartist, 51

The Orphan Drug Act, 7

Therapy, 50

Thiotepa, 31

Thymidine kinase gene, 25

TILS, 21, 22

TNF, 22, 39, 49

TNF-á, 20, 22

TNF-à, 20, 22

Tobacco, 44

Tobacco plant, 43

Tomato ripening, 43

Tomatoes, 32, 43

Toxin-conjugated antibodies, 24

Toxins, 13

Transcription, 27, 32, 33, 37, 38

Transcription factor, 19, 28

Transcription factors, 28

Transcription inhibitor, 33

Transcription inhibitors, 33

Transdermal drug delivery, 42

Transfect, 25

Transfected into plants, 44

Transfecting, 21

Transfection, 21, 22, 38, 42

Transfections, 22

Transformation, 28

Transforming growth factor-á-1, 3

Transforming growth factor-ás, 23, 39

Transgenes, 43, 46

Transgenic, 15, 40, 41, 44, 51

Transgenic cattle, 44

Transgenic fish, 46

Transgenic plant, 43

Translation, 32, 34

Translocations, 28

Transplacental, 33

Transplacental transfer, 17

Transplant, 19

Transplantation, 18

Transplantation immunology, 18

Transplants, 39

Trauma, 48

Triplex formation, 32

Tularik

Inc, 33

Inc., 33

Tumor, 27, 41

Tumor cell, 21, 27

Tumor immunity, 22

Tumor infiltrating lymphocytes, 21

Tumor necrosis factor, 3, 14, 39

Tumor necrosis factors, 22

Tumor regression, 25

Tumor specific antigens, 30

Tumor suppressor, 29

Tumor suppressor genes, 28

Tumor-specific antigens, 29

Tumors, 19, 21, 29

Tyrosine kinase, 27

Tyrosine kinases, 27

U-90

152, 37

U.S. government, 50

Uncoating, 36

United States Biochemical Corp, 34

United States Orphan Drug Act, 7

Univ. of Calif.

Berkeley, 33

Univax Biologicals

Inc., 13

V3 region, 17

Vaccination, 21

Vaccine, 15, 16, 17, 18

Vaccines, 14, 15, 16, 17, 18, 30, 36, 41

Vaccinia vectors, 18

Vaginitis, 32

VALUE-LINE, 61

VaxSyn, 17

Vectors, 18

Venture capital, 29

Vermin, 45

Vertex

Inc., 33

VESTOR, 61

Vibrio, 46

Vibrosis, 46

Viral, 38

Viral enhancer, 33

Viral Technologies

Inc., 16

Viral vector, 41

Virion, 38

Virology, 35

Virus, 13, 16, 18, 32, 36, 37, 38, 41

Virus-infected, 19, 29

Viruses, 15, 35, 37, 38

Vitamin A, 38

Vitamin C, 38

Vitamin E, 38

Vitamins C, 26

Whole virus, 15

Winners, 53

World Intellectual Property Organization, 6

Wound healing, 23, 31, 39, 40

Xoma, 48, 49

Xoma (XOMA), 58

Xoma Corporation (XOMA), 58

Yersinia ruckeri, 46

Zalcitabine, 37

Zidovudine, 37

à-amylase, 44

à-interferon, 44

ç-Interferon, 3

UPGRADE CHANGES.........................................#

CHANGES IN UPGRADE

Release 1.1

Clarifications to AIDS vaccines and minor corrections

Release 1.15

Minor additions and clarifications

Headins for clarifications

Release 1.3

Interleukins and Cytokines added

Reference for antibody conjugate treatment

Clarification of blood-brain barrier drugs

Other minor additions and clarifications

Release 1.4

Table of Contents and an Index was added

Agriculture and biomedicine additions

Minor corrections and clarifications

Release 1.45

Clarification of BIO merger (ABC+IBA)

Agriculture additions

Immunotherapy additions

Release 1.5

Marine Biotechnology added

phase II results of Regeneron's CNTF

AIDS vaccine additions

Release 1.55

Wound healing section added

TGF additions

Transcription enhancing drugs - fetal hemoglobin

minor additions

Release 1.6

Virology Additions, gene therpy

Cell cycle company additions

Biodiversity treaty additions

minor additions and clarifications

Release 1.61

Regeneron phase II result clarification

Antisense patent additions

Release 1.62

Biodiversity treaty ratified

New MS therapies.

Other minor additions and clarifications

Release 1.63

Centoxin and E5 clarification

Failure of Soluble IL 1 receptor in septic shock

Release 1.65

Cephalon addition to NGF description

AIDS vaccine additions

Splicing drugs

Autoimmune disease additions

Agriculture additions

Release 1.7

HIVIG of North American Biologicals for HIV-infected pregnant

Women

Interleukin 12 and AIDS Therapy

Somatix and artificial blood

Other minor corrections and clarifications

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INVESTMENTS IN BIOTECHNOLOGY 1993

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