Current Shareware 1994 January/SHAR194.ISO/textfile/biovst.zip/BIOVST.ASC

Text File | 1993-10-21 | 130KB | 5,204 lines

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






                           1





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


                           2







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-ß-1 (TGF-ß1), 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, τ-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


                           3





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


                           4





(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-


                           5





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.


                           6





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


                           7





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.






                           8





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










                           9





  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




                           10





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




                           11





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


                           12





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




                           13





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




                           14





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


                           15







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


                           16







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


                           17







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


                           18







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


                           19







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-α, EGF,  FGF,  TGF-ß,  TNF-α,TNF-ß,

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  1α,  IL  1ß,  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


                           20







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


                           21







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-τ production.





TNF: Cachectin and lymphotoxin are the  tumor  necrosis  factors,

TNF-α and TNF-ß.  TNF-α 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-ßs:   TGF-ßs have  pleotropic  effects  on  many  cell  types


                           22







including immune cells and fibroblasts.   They  are  involved  in

immune memory, immune suppression and wound healing.

Transforming growth  factor-ßs  (TGF-ßs)  (Genentech:TGF-ß1,  Cel

trix: TGF-ß2, and Oncogene Sciences:TGF-ß3),  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 ß-interferon (IFN-ß1b), 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


                           23







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

of the central  nervous  system.   ß-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


                           24







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


                           25







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 30µg/kg of CNTF, one third was

to receive 15µg/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.......................#


                           26





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




                           27





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




                           28





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




                           29





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




                           30





(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

ß3 (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


                           31







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




                           32





     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, ß-thalassemia and  sickle  cell  anemia.   Fetal  hemo

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

committed to rational-drug design.






                           33









  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


                           34





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-ßs 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


                           35





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


                           36





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


                           37





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


                           38





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-ßs (TGF-ßs)

(Genentech:TGF-ß1, Celtrix: TGF-ß2, and Oncogene Sciences:TGF-

ß3), are members of a family of over 18 proteins.    TGF-ßs 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-ßs 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


                           39





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-ßs are involved in would  healing  (Genen

tech:TGF-ß1,  Celtrix:  TGF-ß2,  and  Oncogene  Sciences:TGF-ß3).

Oncogene Sciences, Inc. is developing  the  use  of  TGF-ß3  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


                           40





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


                           41





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:




                           42





     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


                           43





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 α-amylase and Michigan State  Univers

ity, in collaboration with Miescher Institute in  Basel,  Switzer

land have produced  turnips  which  produce  human  α-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.


                           44





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


                           45





     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:


                           46







     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.


                           47





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


                           48





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.


                           49





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


                           50





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


                           51





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.














                           52





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 [phone]

or [phone].





                           53





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  2.8Å  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):



                           54






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.


                           55






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.






                           56





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)














                           57





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







                           58





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.






                           59








APPENDIX C (CONTINUED):


                      CompuServe Databases

DISCLOSURE

VALUE-LINE


                         GEnie Databases

VESTOR

Dow Jones/News Retrieval










































                           60





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.















































                           61





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




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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.



























                           62





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


                           63





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


                           64





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


                           65





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


                           66





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


                           67






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


                           68





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-ß1b, 23
IgE, 21
IGF, 20
IGF-1, 3
IL 1, 49
IL 1ra, 49
IL 2, 20, 21, 22, 42
IL 2 receptor, 19


                           69





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-τ, 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



                           70





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


                           71





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


                           72





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


                           73





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


                           74





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


                           75





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

ß-interferon, 23, 24
ß-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-ß, 20
TGF-ß1, 3, 23, 39, 40
TGF-ß2, 23, 39, 40
TGF-ß3, 23, 31, 39, 40
TGF-ßs, 22, 23, 39, 40
TGF-α, 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-ß, 20, 22
TNF-α, 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


                           76





Transforming growth factor-ß-1, 3
Transforming growth factor-ßs, 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


                           77





  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

α-amylase, 44
α-interferon, 44
τ-Interferon, 3
























                           78





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


                           79





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












































                           80